Study to Assess the Effect of Rifampicin on Blood Levels and Safety of AZD9291, in Patients With EGFRm+ NSCLC
Sponsor
AstraZeneca (Industry)
Overall Status
Completed
CT.gov ID
NCT02197247
Collaborator
(none)
41
18
1
77.7
2.3
0
Study Details
Study Description
Brief Summary
This is a Phase I, open-label, 2-part study in patients with a confirmed diagnosis of epidermal growth factor receptor (EGFR) mutation positive (EGFRm+) non-small cell lung cancer (NSCLC), who have progressed following prior therapy with an approved EGFR tyrosine kinase inhibitor (TKI) agent.
Part A will assess the effect of rifampicin on the pharmacokinetic (PK) parameters of AZD9291 and metabolites AZ5104 and AZ7550 following multiple oral dosing of both rifampicin and AZD9291 in a fasted state.
Part B will allow patients further access to AZD9291 after the PK phase (Part A) and will provide for additional safety data collection. All patients who complete Part A will be able to enter part B, and continue to receive AZD9291 80 mg once daily until: disease progression; they are no longer deriving clinical benefit; or any other reason.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
Study Design
Study Type:
Interventional
Actual Enrollment
:
41 participants
Masking:
None (Open Label)
Primary Purpose:
Other
Official Title:
A Phase I, Open-Label, Non-Randomised, Multicentre Study to Assess the Effect of Rifampicin (a CYP3A4 Inducer) on the Pharmacokinetics of AZD9291 in Patients With EGFRm Positive NSCLC Whose Disease Has Progressed on an EGFR TKI
Actual Study Start Date
:
Dec 4, 2014
Actual Primary Completion Date
:
Jul 9, 2015
Actual Study Completion Date
:
May 26, 2021
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Rifampicin and AZD9291 Sequential treatments of AZD9291 alone followed by AZD9291 +rifampicin, followed by AZD9291 alone. |
Procedure: Pharmacokinetic sampling - AZD9291
Blood sampling to measure AZD9291
Drug: Rifampicin
Rifampicin (CYP inducer) 600mg taken once daily from Day 29 to Day 49 (Part A)
Drug: AZD9291 tablet dosing
Part A: AZD9291 80mg tablet taken daily from Days 1 to 77. Part B: AZD9291 80mg tablet taken daily for 12 months.
Procedure: Pharmacokinetic sampling - rifampicin
Blood sampling to measure rifampicin levels
Procedure: Pharmacokinetic sampling - AZ5140 and AZ7550
Blood samples to measure levels of AZ5140 and AZ7550
|
Outcome Measures
Primary Outcome Measures
- Assessment of Maximum Plasma Concentration for AZD9291 After Dosing Alone and in Combination With Rifampicin (Css,Max) [Samples collected on Day 28 following AZD9291 alone and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.]
Rate and extent of absorption of AZD9291 by assessment of maximum plasma concentration at steady state (Css,max). AZD9291 doses were first without, then with rifampicin (Periods 1 and 2, respectively).
- Assessment of Area Under the Plasma Concentration-time Curve During the Dosing Interval for AZD9291 After Dosing Alone and in Combination With Rifampicin (AUCtau) [Samples collected on Day 28 following AZD9291 alone and Day 49 following AZD9291 and rifampicin at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.]
Rate and extent of absorption of AZD9291 by assessment of AUCtau. AZD9291 doses were first without, then with rifampicin (Periods 1 and 2, respectively).
Secondary Outcome Measures
- Assessment of Css,Max for AZD9291 Before and After Rifampicin [Samples collected on Day 28 and 77 following AZD9291 alone at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.]
Rate and extent of absorption of AZD9291 by assessment of Css,max. AZD9291 alone before rifampicin (Period 1) and AZD9291 alone after rifampicin (Period 3).
- Assessment of Css,Max for AZ5104 (Metabolite) [Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.]
Rate and extent of absorption of AZ5104 (metabolite) by assessment of Css,max. AZD9291 dosing alone and in combination with rifampicin (all periods).
- Assessment of Css,Max for AZ7550 (Metabolite) [Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.]
Rate and extent of absorption of AZ7550 (metabolite) by assessment of Css,max. AZD9291 dosing alone and in combination with rifampicin (all periods).
- Assessment of Css,Max for Rifampicin [Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.]
Rate and extent of absorption of rifampicin by assessment of Css,max. AZD9291 dosing in combination with rifampicin (Period 2).
- Assessment of AUCtau for AZD9291 Before and After Rifampicin [Samples collected on Day 28 and 77 following AZD9291 alone at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.]
Rate and extent of absorption of AZD9291 by assessment of AUCtau. AZD9291 alone before rifampicin (Period 1) and AZD9291 alone after rifampicin (Period 3).
- Assessment of AUCtau for AZ5104 (Metabolite) [Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.]
Rate and extent of absorption of AZ5104 (metabolite) by assessment of AUCtau. AZD9291 dosing alone and in combination with rifampicin (all periods).
- Assessment of AUCtau for AZ7550 (Metabolite) [Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.]
Rate and extent of absorption of AZ7550 (metabolite) by assessment of AUCtau. AZD9291 dosing alone and in combination with rifampicin (all periods).
- Assessment of AUCtau for Rifampicin [Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.]
Rate and extent of absorption of rifampicin by assessment of AUCtau. AZD9291 dosing in combination with rifampicin (Period 2).
- Assessment of Tss,Max for AZD9291, and AZ5104 and AZ7550 (Metabolites) [Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.]
Rate and extent of absorption of AZD9291, and AZ5104 and AZ7550 (metabolites) by assessment of time to reach maximum plasma concentration at steady state (tss,max). AZD9291 dosing alone and in combination with rifampicin (all periods).
- Assessment of Tss,Max for Rifampicin [Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.]
Rate and extent of absorption of rifampicin by assessment of tss,max. AZD9291 dosing in combination with rifampicin (Period 2).
- Assessment of Css,Min for AZD9291, and AZ5104 and AZ7550 (Metabolites) [Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.]
Rate and extent of absorption of AZD9291, and AZ5104 and AZ7550 (metabolites) by assessment of minimum plasma concentration at steady state (Css,min). AZD9291 dosing alone and in combination with rifampicin (all periods).
- Assessment of Css,Min for Rifampicin [Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.]
Rate and extent of absorption of rifampicin by assessment of minimum plasma concentration at steady state (Css,min). AZD9291 dosing in combination with rifampicin (Period 2).
- Assessment of CLss/F for AZD9291 [Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.]
Rate and extent of absorption of AZD9291 by assessment of the apparent plasma clearance following oral administration and multiple dosing (CLss/F). AZD9291 dosing alone and in combination with rifampicin (all periods).
- Assessment of CLss/F for Rifampicin [Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.]
Rate and extent of absorption of rifampicin by assessment of CLss/F. AZD9291 dosing in combination with rifampicin (Period 2).
- Assessment of the Metabolic Ratios of Css,Max for AZ5104 and AZ7550 (MRCss,Max) [Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.]
Assessment of the metabolite to parent ratio (calculated as AZ5104 to AZD9291 and AZ7550 to AZD9291) for Css,max (MRCss,max). AZD9291 dosing alone and in combination with rifampicin (all periods).
- Assessment of the Metabolic Ratios of AUCtau for AZ5104 and AZ7550 (MRAUCtau) [Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.]
Assessment of the metabolite to parent ratio (calculated as AZ5104 to AZD9291 and AZ7550 to AZD9291) for AUCtau (MRAUCtau). AZD9291 dosing alone and in combination with rifampicin (all periods).
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
to 130 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
For inclusion in the study patient should fulfil the following criteria:
-
Male or female, aged at least 18 years. 2. Histological or cytological confirmation diagnosis of NSCLC. 3. Radiological documentation of disease progression while on a previous continuous treatment with an EGFR TKI, eg gefitinib, erlotinib or afatinib. In addition, other lines of therapy may have been given. All patients must have documented radiological progression on the last treatment administered prior to enrolling in the study.
-
Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q).
-
Eastern Cooperative Oncology Group (ECOG) performance status 0-1 with no deterioration over the previous 2 weeks (Appendix G).
-
Patients must have a life expectancy of ≥12 weeks as estimated at the time of screening.
-
Females should be using adequate contraceptive measures and must have a negative pregnancy test prior to start of dosing if of child-bearing potential, or must have evidence of non-child-bearing potential by fulfilling one of the following criteria at screening: Post-menopausal defined as aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments. Women under 50 years old would be considered post-menopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and with LH and FSH levels in the post-menopausal range for the institution. Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy, but not tubal ligation.
-
Male patients should be willing to use barrier contraception, ie, condoms, until 6 months after last study drug is taken.
-
Contact lens wearers must be prepared to not wear contact lenses and wear glasses for the duration of the rifampicin dosing.
-
Participation in another clinical study with an IP during the last 14 days (or a longer period depending on the defined characteristics of the agents used).
-
Treatment with any of the following: Treatment with an EGFR TKI (eg, erlotinib or gefitinib) w/in 8 days or approx. 5 x half-life, whichever is the longer, of the first dose of study treatment; any cytotoxic chemo, investigational agents or other anticancer drugs from a previous treatment regimen w/in 14 days of the first dose of study treatment; major surgery (excluding placement of vascular access) w/in 4 weeks of the first dose of study treatment; radiotherapy with a limited field of radiation for palliation w/in 1 week of the first dose of study treatment, with the exception of patients receiving radiation to more than 30% of bone marrow or with a wide field of radiation which must be completed w/in 4 weeks of the first; patients currently receiving (or unable to stop use prior to receiving the first dose) medications or herbal supplements known to be potent inhibitors of CYP3A4 (at least 1 week prior) and potent inducers of CYP3A4 (at least 3 week prior). All patients must avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer/inhibitory effects on CYP3A4.
-
Any unresolved toxicities from prior therapy greater than CTCAE Grade 1 at the time of starting study treatment with the exception of alopecia and Grade 2, prior platinum-therapy related neuropathy.
-
Any intake of grapefruit, grapefruit juice, Seville oranges, Seville orange marmalade, or other products containing grapefruit or Seville oranges within 7 days of the first administration of the IP until the final PK sample collection on Day 78 of Part A.
-
Spinal cord compression or brain metastases unless asymptomatic, stable and not requiring steroids for at least 4 weeks prior to start of study treatment.
-
Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses, which in the Investigator's opinion makes it undesirable for the patient to participate in the study or which would jeopardise compliance with the protocol, or active infection including hepatitis B, hepatitis C and HIV. Screening for chronic conditions is not required.
-
Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values: ANC <1.5 x 109/L; Platelet count <100 x 109/L; Haemoglobin <90 g/L; ALT >2.5 times the ULN if no demonstrable liver metastases or >5 times ULN in the presence of liver metastases; AST >2.5 times ULN if no demonstrable liver metastases or >5 times ULN in the presence of liver metastases; Total bilirubin
1.5 times ULN if no liver metastases or >3 times ULN in the presence of documented Gilbert's Syndrome (unconjugated hyperbilirubinaemia) or liver metastases; creatinine 1.5 times ULN concurrent with creatinine clearance <50 ml/min (measured or calculated by Cockcroft and Gault equation); confirmation of creatinine clearance is only required when creatinine is >1.5 times ULN.
-
Any of the following cardiac criteria: Mean resting corrected QT interval corrected for heart rate using Fridericia's correction factor (QTcF) >470 msec obtained from 3 electrocardiograms (ECGs); any clinically important abnormalities in rhythm, conduction or morphology of resting ECG eg, complete left bundle branch block, third degree heart block, second degree heart block, PR interval >250 msec; any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age or any concomitant medication known to prolong the QT interval.
-
Patients unable to swallow oral medication or patients with GI disorders or significant GI resection likely to interfere with the absorption of AZD9291.
-
Past medical history of ILD, drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD.
-
Women who are breastfeeding.
-
Patients with a known hypersensitivity to AZD9291 or rifampicin or any of the excipients of the products.
-
Concomitant medication contraindicated for use with rifampicin (including, but not limited to): cisapride, oral midazolam, nisoldipine, pimozide, quinidine, dofetilide, triazolam, levacetylmethadol (levomethadyl), 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA)-reductase inhibitors metabolised by CYP3A4, such as lovastatin and simvastatin, ergot alkaloids metabolised by CYP3A4, such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine).
-
For optional genetic research: .Previous allogenic bone marrow transplant or Non-leukocyte depleted whole blood transfusion within 120 days of the date of the genetic sample collection.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Research Site | Atlanta | Georgia | United States | 30322 |
| 2 | Research Site | Detroit | Michigan | United States | 48202 |
| 3 | Research Site | Seongnam-si | Korea, Republic of | 13620 | |
| 4 | Research Site | Seoul | Korea, Republic of | 03722 | |
| 5 | Research Site | Seoul | Korea, Republic of | 06351 | |
| 6 | Research Site | Amsterdam | Netherlands | 1066 CX | |
| 7 | Research Site | Maastricht | Netherlands | 6229 HX | |
| 8 | Research Site | Barcelona | Spain | 08041 | |
| 9 | Research Site | L'Hospitalet de Llobregat | Spain | 08908 | |
| 10 | Research Site | Madrid | Spain | 28040 | |
| 11 | Research Site | Madrid | Spain | 28041 | |
| 12 | Research Site | Madrid | Spain | 28046 | |
| 13 | Research Site | Málaga | Spain | 29010 | |
| 14 | Research Site | Sevilla | Spain | 41013 | |
| 15 | Research Site | Taipei | Taiwan | 10002 | |
| 16 | Research Site | Taipei | Taiwan | 112 | |
| 17 | Research Site | Cardiff | United Kingdom | CF14 2TL | |
| 18 | Research Site | Manchester | United Kingdom | M20 4BX |
Sponsors and Collaborators
- AstraZeneca
Investigators
- Study Director: Serban Ghiorghiu, MSD, AstraZeneca
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.Responsible Party:
AstraZeneca
ClinicalTrials.gov Identifier:
NCT02197247
Other Study ID Numbers:
- D5160C00013
- 2014-001525-32
First Posted:
Jul 22, 2014
Last Update Posted:
Jul 12, 2021
Last Verified:
Jun 1, 2021
Individual Participant Data (IPD) Sharing Statement:
Yes
Plan to Share IPD:
Yes
Keywords provided by AstraZeneca
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | First patient enrolled: 04 December 2014; Last Subject Last Visit Part A: 09 July 2015 and Part B: 29 June 2016. Study performed at 18 sites across Asia, North America and Western Europe. Part A assessed effect of multiple doses of rifampicin on PK of AZD9291; Part B allowed subjects further access to AZD9291 and provided additional safety data. |
|---|---|
| Pre-assignment Detail | 51 patients were enrolled (signed informed consent). Patients were assigned to treatment if they met all the inclusion and none of the exclusion criteria. 10 subjects were enrolled but failed inclusion/exclusion criteria and so were not eligible to be assigned treatment. The remaining 41 patients started Period 1 and received treatment. |
| Arm/Group Title | AZD9291 and Rifampicin (Part A); AZD9291 Alone (Part B) |
|---|---|
| Arm/Group Description | In Part A of the study, sequential treatments of AZD9291 alone, followed by AZD9291 + rifampicin, followed by AZD9291 alone. Each patient received 80 mg oral doses of AZD9291 tablets once daily for 77 days (Days 1 to 77) and additionally received 600 mg oral doses of rifampicin once daily on Days 29 to 49. In Part B of the study, each patient received 80 mg oral AZD9291 tablet formulation once daily, for the duration of their participation. |
| Period Title: Part A: Day 1-28 (AZD9291 Alone) | |
| STARTED | 41 |
| COMPLETED | 41 |
| NOT COMPLETED | 0 |
| Period Title: Part A: Day 1-28 (AZD9291 Alone) | |
| STARTED | 41 |
| COMPLETED | 37 |
| NOT COMPLETED | 4 |
| Period Title: Part A: Day 1-28 (AZD9291 Alone) | |
| STARTED | 37 |
| COMPLETED | 32 |
| NOT COMPLETED | 5 |
| Period Title: Part A: Day 1-28 (AZD9291 Alone) | |
| STARTED | 34 |
| COMPLETED | 19 |
| NOT COMPLETED | 15 |
Baseline Characteristics
| Arm/Group Title | AZD9291 and Rifampicin (Part A); AZD9291 Alone (Part B) |
|---|---|
| Arm/Group Description | In Part A of the study, sequential treatments of AZD9291 alone, followed by AZD9291 + rifampicin, followed by AZD9291 alone. Each patient received 80 mg oral doses of AZD9291 tablets once daily for 77 days (Days 1 to 77) and additionally received 600 mg oral doses of rifampicin once daily on Days 29 to 49. In Part B of the study, each patient received 80 mg oral AZD9291 tablet formulation once daily, for the duration of their participation. |
| Overall Participants | 41 |
| Age (years) [Mean (Standard Deviation) ] | |
| Mean (Standard Deviation) [years] |
62.5
(11.74)
|
| Sex: Female, Male (Count of Participants) | |
| Female |
32
78%
|
| Male |
9
22%
|
| Race (NIH/OMB) (Count of Participants) | |
| American Indian or Alaska Native |
0
0%
|
| Asian |
15
36.6%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
| Black or African American |
2
4.9%
|
| White |
24
58.5%
|
| More than one race |
0
0%
|
| Unknown or Not Reported |
0
0%
|
Outcome Measures
| Title | Assessment of Maximum Plasma Concentration for AZD9291 After Dosing Alone and in Combination With Rifampicin (Css,Max) |
|---|---|
| Description | Rate and extent of absorption of AZD9291 by assessment of maximum plasma concentration at steady state (Css,max). AZD9291 doses were first without, then with rifampicin (Periods 1 and 2, respectively). |
| Time Frame | Samples collected on Day 28 following AZD9291 alone and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A. |
Outcome Measure Data
| Analysis Population Description |
|---|
| The PK analysis set included all dosed patients who had at least 1 quantifiable plasma concentration collected post-dose without any important deviations or events that would exclude the patient. |
| Arm/Group Title | AZD9291 Alone (Period 1) | AZD9291 + Rifampicin (Period 2) |
|---|---|---|
| Arm/Group Description | AZD9291 80 mg once daily on Days 1 to 28 (Part A). AZD9291 was administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 28. | Concomitant treatment with AZD9291 80 mg once daily and rifampicin 600 mg once daily on Days 29 to 49 (Part A). All treatments (AZD9291 and rifampicin) were administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 49. |
| Measure Participants | 38 | 32 |
| Geometric Mean (Geometric Coefficient of Variation) [nanomolar (nM)] |
577.4
(44.7)
|
147.5
(48.2)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | AZD9291 Alone (Period 1), AZD9291 + Rifampicin (Period 2) |
|---|---|---|
| Comments | Natural log-transformed Css,max values were compared between periods using a mixed effects analysis of variance (ANOVA) with period as fixed effect and patient as random effect. It was assumed the within-patient coefficient of variation for AZD9291 in both area under the plasma concentration-time curve during the dosing interval (AUCtau) and Cmax was 34%. A 33% decrease in exposure for AZD9291 when given with rifampicin was also assumed. | |
| Type of Statistical Test | Non-Inferiority or Equivalence (legacy) | |
| Comments | No effect on the PK of AZD9291 after co-administration of rifampicin was concluded if the lower bound of the 90% confidence intervals (CIs) for the ratios (Period 2 versus Period 1) of AZD9291 AUCtau and Css,max were both above 50%. The experiment-wide power for the ratios being above 50% was 90% (95% power for each parameter). | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Geometric least-squares (LS) mean ratio |
| Estimated Value | 27.16 | |
| Confidence Interval |
(2-Sided) 90% 24.36 to 30.29 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | AZD9291+rifampicin / AZD9291 alone (Period 2 versus Period 1). | |
| Title | Assessment of Area Under the Plasma Concentration-time Curve During the Dosing Interval for AZD9291 After Dosing Alone and in Combination With Rifampicin (AUCtau) |
|---|---|
| Description | Rate and extent of absorption of AZD9291 by assessment of AUCtau. AZD9291 doses were first without, then with rifampicin (Periods 1 and 2, respectively). |
| Time Frame | Samples collected on Day 28 following AZD9291 alone and Day 49 following AZD9291 and rifampicin at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A. |
Outcome Measure Data
| Analysis Population Description |
|---|
| The PK analysis set included all dosed patients who had at least 1 quantifiable plasma concentration collected post-dose without any important deviations or events that would exclude the patient. |
| Arm/Group Title | AZD9291 Alone (Period 1) | AZD9291 + Rifampicin (Period 2) |
|---|---|---|
| Arm/Group Description | AZD9291 80 mg once daily on Days 1 to 28 (Part A). AZD9291 was administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 28. | Concomitant treatment with AZD9291 80 mg once daily and rifampicin 600 mg once daily on Days 29 to 49 (Part A). All treatments (AZD9291 and rifampicin) were administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 49. |
| Measure Participants | 38 | 32 |
| Geometric Mean (Geometric Coefficient of Variation) [nM * hour (nM*h)] |
10870
(44.3)
|
2192
(43.8)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | AZD9291 Alone (Period 1), AZD9291 + Rifampicin (Period 2) |
|---|---|---|
| Comments | Natural log-transformed AUCtau values were compared between periods using a mixed effects ANOVA with period as fixed effect and patient as random effect. It was assumed the within-patient coefficient of variation for AZD9291 in both AUCtau and Cmax was 34%. A 33% decrease in exposure for AZD9291 when given with rifampicin was also assumed. | |
| Type of Statistical Test | Non-Inferiority or Equivalence (legacy) | |
| Comments | No effect on the PK of AZD9291 after co-administration of rifampicin was concluded if the lower bound of the 90% CIs for the ratios (Period 2 versus Period 1) of AZD9291 AUCtau and Css,max were both above 50%. The experiment-wide power for the ratios being above 50% was 90% (95% power for each parameter). | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Geometric LS Mean Ratio |
| Estimated Value | 21.55 | |
| Confidence Interval |
(2-Sided) 90% 19.50 to 23.83 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | AZD9291+rifampicin / AZD9291 alone (Period 2 versus Period 1). | |
| Title | Assessment of Css,Max for AZD9291 Before and After Rifampicin |
|---|---|
| Description | Rate and extent of absorption of AZD9291 by assessment of Css,max. AZD9291 alone before rifampicin (Period 1) and AZD9291 alone after rifampicin (Period 3). |
| Time Frame | Samples collected on Day 28 and 77 following AZD9291 alone at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A. |
Outcome Measure Data
| Analysis Population Description |
|---|
| The PK analysis set included all dosed patients who had at least 1 quantifiable plasma concentration collected post-dose without any important deviations or events that would exclude the patient. |
| Arm/Group Title | AZD9291 Alone (Period 1) | AZD9291 Alone (Period 3) |
|---|---|---|
| Arm/Group Description | AZD9291 80 mg once daily on Days 1 to 28 (Part A). AZD9291 was administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 28. | AZD9291 80 mg once daily on Days 50 to 77 (Part A). AZD9291 was administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 77. |
| Measure Participants | 38 | 28 |
| Geometric Mean (Geometric Coefficient of Variation) [nM] |
577.4
(44.7)
|
531.4
(37.9)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | AZD9291 Alone (Period 1), AZD9291 + Rifampicin (Period 2) |
|---|---|---|
| Comments | Natural log-transformed Css,max values were compared between periods using a mixed effects ANOVA with period as a fixed effect and patient as a random effect. | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Geometric LS Mean Ratio |
| Estimated Value | 95.53 | |
| Confidence Interval |
(2-Sided) 90% 85.27 to 107.03 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | AZD9291 alone / AZD9291 alone (Period 3 versus Period 1). No pre-specified margins for equivalence test for AZD9291 alone in separate periods, but analysed for consistency with AZD9291+rifampicin / AZD9291 alone analysis (primary outcome measure). | |
| Title | Assessment of Css,Max for AZ5104 (Metabolite) |
|---|---|
| Description | Rate and extent of absorption of AZ5104 (metabolite) by assessment of Css,max. AZD9291 dosing alone and in combination with rifampicin (all periods). |
| Time Frame | Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A. |
Outcome Measure Data
| Analysis Population Description |
|---|
| The PK analysis set included all dosed patients who had at least 1 quantifiable plasma concentration collected post-dose without any important deviations or events that would exclude the patient. |
| Arm/Group Title | AZD9291 Alone (Period 1) | AZD9291 + Rifampicin (Period 2) | AZD9291 Alone (Period 3) |
|---|---|---|---|
| Arm/Group Description | AZD9291 80 mg once daily on Days 1 to 28 (Part A). AZD9291 was administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 28. | Concomitant treatment with AZD9291 80 mg once daily and rifampicin 600 mg once daily on Days 29 to 49 (Part A). All treatments (AZD9291 and rifampicin) were administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 49. | AZD9291 80 mg once daily on Days 50 to 77 (Part A). AZD9291 was administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 77. |
| Measure Participants | 38 | 32 | 28 |
| Geometric Mean (Geometric Coefficient of Variation) [nM] |
60.40
(57.2)
|
12.28
(52.6)
|
50.73
(49.8)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | AZD9291 Alone (Period 1), AZD9291 + Rifampicin (Period 2) |
|---|---|---|
| Comments | For AZ5104 (metabolite), natural log-transformed Css,max values were compared between periods using a mixed effects ANOVA with period as a fixed effect and patient as a random effect. | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Geometric LS Mean Ratio |
| Estimated Value | 21.72 | |
| Confidence Interval |
(2-Sided) 90% 19.08 to 24.72 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | AZD9291+rifampicin / AZD9291 alone (Period 2 versus Period 1). No pre-specified margins for equivalence test for metabolites, but analysed for consistency with AZD9291 analysis. | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | AZD9291 Alone (Period 1), AZD9291 Alone (Period 3) |
|---|---|---|
| Comments | For AZ5104 (metabolite), natural log-transformed Css,max values were compared between periods using a mixed effects ANOVA with period as a fixed effect and patient as a random effect. | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Geometric LS Mean Ratio |
| Estimated Value | 88.31 | |
| Confidence Interval |
(2-Sided) 90% 77.17 to 101.07 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | AZD9291 alone / AZD9291 alone (Period 3 versus Period 1). No pre-specified margins for equivalence test for metabolites, but analysed for consistency with AZD9291 analysis. | |
| Title | Assessment of Css,Max for AZ7550 (Metabolite) |
|---|---|
| Description | Rate and extent of absorption of AZ7550 (metabolite) by assessment of Css,max. AZD9291 dosing alone and in combination with rifampicin (all periods). |
| Time Frame | Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A. |
Outcome Measure Data
| Analysis Population Description |
|---|
| The PK analysis set included all dosed patients who had at least 1 quantifiable plasma concentration collected post-dose without any important deviations or events that would exclude the patient. |
| Arm/Group Title | AZD9291 Alone (Period 1) | AZD9291 + Rifampicin (Period 2) | AZD9291 Alone (Period 3) |
|---|---|---|---|
| Arm/Group Description | AZD9291 80 mg once daily on Days 1 to 28 (Part A). AZD9291 was administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 28. | Concomitant treatment with AZD9291 80 mg once daily and rifampicin 600 mg once daily on Days 29 to 49 (Part A). All treatments (AZD9291 and rifampicin) were administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 49. | AZD9291 80 mg once daily on Days 50 to 77 (Part A). AZD9291 was administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 77. |
| Measure Participants | 38 | 32 | 28 |
| Geometric Mean (Geometric Coefficient of Variation) [nM] |
53.54
(43.7)
|
73.14
(25.0)
|
53.24
(34.4)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | AZD9291 Alone (Period 1), AZD9291 + Rifampicin (Period 2) |
|---|---|---|
| Comments | For AZ7550 (metabolite), natural log-transformed Css,max values were compared between periods using a mixed effects ANOVA with period as a fixed effect and patient as a random effect. | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Geometric LS Mean Ratio |
| Estimated Value | 139.32 | |
| Confidence Interval |
(2-Sided) 90% 127.74 to 151.96 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | AZD9291+rifampicin / AZD9291 alone (Period 2 versus Period 1). No pre-specified margins for equivalence test for metabolites, but analysed for consistency with AZD9291 analysis. | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | AZD9291 Alone (Period 1), AZD9291 Alone (Period 3) |
|---|---|---|
| Comments | For AZ7550 (metabolite), natural log-transformed Css,max values were compared between periods using a mixed effects ANOVA with period as a fixed effect and patient as a random effect. | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Geometric LS Mean Ratio |
| Estimated Value | 100.75 | |
| Confidence Interval |
(2-Sided) 90% 92.04 to 110.29 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | AZD9291 alone / AZD9291 alone (Period 3 versus Period 1). No pre-specified margins for equivalence test for metabolites, but analysed for consistency with AZD9291 analysis. | |
| Title | Assessment of Css,Max for Rifampicin |
|---|---|
| Description | Rate and extent of absorption of rifampicin by assessment of Css,max. AZD9291 dosing in combination with rifampicin (Period 2). |
| Time Frame | Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A. |
Outcome Measure Data
| Analysis Population Description |
|---|
| The PK analysis set included all dosed patients who had at least 1 quantifiable plasma concentration collected post-dose without any important deviations or events that would exclude the patient. |
| Arm/Group Title | AZD9291 + Rifampicin (Period 2) |
|---|---|
| Arm/Group Description | Concomitant treatment with AZD9291 80 mg once daily and rifampicin 600 mg once daily on Days 29 to 49 (Part A). All treatments (AZD9291 and rifampicin) were administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 49. |
| Measure Participants | 32 |
| Geometric Mean (Geometric Coefficient of Variation) [nanogram per millilitre (ng/mL)] |
13810
(40.6)
|
| Title | Assessment of AUCtau for AZD9291 Before and After Rifampicin |
|---|---|
| Description | Rate and extent of absorption of AZD9291 by assessment of AUCtau. AZD9291 alone before rifampicin (Period 1) and AZD9291 alone after rifampicin (Period 3). |
| Time Frame | Samples collected on Day 28 and 77 following AZD9291 alone at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A. |
Outcome Measure Data
| Analysis Population Description |
|---|
| The PK analysis set included all dosed patients who had at least 1 quantifiable plasma concentration collected post-dose without any important deviations or events that would exclude the patient. |
| Arm/Group Title | AZD9291 Alone (Period 1) | AZD9291 Alone (Period 3) |
|---|---|---|
| Arm/Group Description | AZD9291 80 mg once daily on Days 1 to 28 (Part A). AZD9291 was administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 28. | AZD9291 80 mg once daily on Days 50 to 77 (Part A). AZD9291 was administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 77. |
| Measure Participants | 38 | 28 |
| Geometric Mean (Geometric Coefficient of Variation) [nM*h] |
10870
(44.3)
|
10060
(36.8)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | AZD9291 Alone (Period 1), AZD9291 + Rifampicin (Period 2) |
|---|---|---|
| Comments | Natural log-transformed AUCtau values were compared between periods using a mixed effects ANOVA with period as a fixed effect and patient as a random effect. | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Geometric LS Mean Ratio |
| Estimated Value | 95.89 | |
| Confidence Interval |
(2-Sided) 90% 86.37 to 106.45 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | AZD9291 alone / AZD9291 alone (Period 3 versus Period 1). No pre-specified margins for equivalence test for AZD9291 alone in separate periods, but analysed for consistency with AZD9291+rifampicin / AZD9291 alone analysis (primary outcome measure). | |
| Title | Assessment of AUCtau for AZ5104 (Metabolite) |
|---|---|
| Description | Rate and extent of absorption of AZ5104 (metabolite) by assessment of AUCtau. AZD9291 dosing alone and in combination with rifampicin (all periods). |
| Time Frame | Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A. |
Outcome Measure Data
| Analysis Population Description |
|---|
| The PK analysis set included all dosed patients who had at least 1 quantifiable plasma concentration collected post-dose without any important deviations or events that would exclude the patient. |
| Arm/Group Title | AZD9291 Alone (Period 1) | AZD9291 + Rifampicin (Period 2) | AZD9291 Alone (Period 3) |
|---|---|---|---|
| Arm/Group Description | AZD9291 80 mg once daily on Days 1 to 28 (Part A). AZD9291 was administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 28. | Concomitant treatment with AZD9291 80 mg once daily and rifampicin 600 mg once daily on Days 29 to 49 (Part A). All treatments (AZD9291 and rifampicin) were administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 49. | AZD9291 80 mg once daily on Days 50 to 77 (Part A). AZD9291 was administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 77. |
| Measure Participants | 38 | 32 | 28 |
| Geometric Mean (Geometric Coefficient of Variation) [nM*h] |
1206
(55.8)
|
210.3
(48.0)
|
1029
(49.7)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | AZD9291 Alone (Period 1), AZD9291 + Rifampicin (Period 2) |
|---|---|---|
| Comments | For AZ5104 (metabolite), natural log-transformed AUCtau values were compared between periods using a mixed effects ANOVA with period as a fixed effect and patient as a random effect. | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Geometric LS Mean Ratio |
| Estimated Value | 18.76 | |
| Confidence Interval |
(2-Sided) 90% 16.61 to 21.19 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | AZD9291+rifampicin / AZD9291 alone (Period 2 versus Period 1). No pre-specified margins for equivalence test for metabolites, but analysed for consistency with AZD9291 analysis. | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | AZD9291 Alone (Period 1), AZD9291 Alone (Period 3) |
|---|---|---|
| Comments | For AZ5104 (metabolite), natural log-transformed AUCtau values were compared between periods using a mixed effects ANOVA with period as a fixed effect and patient as a random effect. | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Geometric LS Mean Ratio |
| Estimated Value | 90.08 | |
| Confidence Interval |
(2-Sided) 90% 79.34 to 102.27 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | AZD9291 alone / AZD9291 alone (Period 3 versus Period 1). No pre-specified margins for equivalence test for metabolites, but analysed for consistency with AZD9291 analysis. | |
| Title | Assessment of AUCtau for AZ7550 (Metabolite) |
|---|---|
| Description | Rate and extent of absorption of AZ7550 (metabolite) by assessment of AUCtau. AZD9291 dosing alone and in combination with rifampicin (all periods). |
| Time Frame | Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A. |
Outcome Measure Data
| Analysis Population Description |
|---|
| The PK analysis set included all dosed patients who had at least 1 quantifiable plasma concentration collected post-dose without any important deviations or events that would exclude the patient. |
| Arm/Group Title | AZD9291 Alone (Period 1) | AZD9291 + Rifampicin (Period 2) | AZD9291 Alone (Period 3) |
|---|---|---|---|
| Arm/Group Description | AZD9291 80 mg once daily on Days 1 to 28 (Part A). AZD9291 was administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 28. | Concomitant treatment with AZD9291 80 mg once daily and rifampicin 600 mg once daily on Days 29 to 49 (Part A). All treatments (AZD9291 and rifampicin) were administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 49. | AZD9291 80 mg once daily on Days 50 to 77 (Part A). AZD9291 was administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 77. |
| Measure Participants | 38 | 32 | 28 |
| Geometric Mean (Geometric Coefficient of Variation) [nM*h] |
1107
(41.7)
|
1416
(25.6)
|
1111
(31.7)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | AZD9291 Alone (Period 1), AZD9291 + Rifampicin (Period 2) |
|---|---|---|
| Comments | For AZ7550 (metabolite), natural log-transformed AUCtau values were compared between periods using a mixed effects ANOVA with period as a fixed effect and patient as a random effect. | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Geometric LS Mean Ratio |
| Estimated Value | 129.81 | |
| Confidence Interval |
(2-Sided) 90% 119.14 to 141.44 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | AZD9291+rifampicin / AZD9291 alone (Period 2 versus Period 1). No pre-specified margins for equivalence test for metabolites, but analysed for consistency with AZD9291 analysis. | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | AZD9291 Alone (Period 1), AZD9291 Alone (Period 3) |
|---|---|---|
| Comments | For AZ7550 (metabolite), natural log-transformed AUCtau values were compared between periods using a mixed effects ANOVA with period as a fixed effect and patient as a random effect. | |
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Geometric LS Mean Ratio |
| Estimated Value | 100.76 | |
| Confidence Interval |
(2-Sided) 90% 92.15 to 110.19 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | AZD9291 alone / AZD9291 alone (Period 3 versus Period 1). No pre-specified margins for equivalence test for metabolites, but analysed for consistency with AZD9291 analysis. | |
| Title | Assessment of AUCtau for Rifampicin |
|---|---|
| Description | Rate and extent of absorption of rifampicin by assessment of AUCtau. AZD9291 dosing in combination with rifampicin (Period 2). |
| Time Frame | Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A. |
Outcome Measure Data
| Analysis Population Description |
|---|
| The PK analysis set included all dosed patients who had at least 1 quantifiable plasma concentration collected post-dose without any important deviations or events that would exclude the patient. |
| Arm/Group Title | AZD9291 + Rifampicin (Period 2) |
|---|---|
| Arm/Group Description | Concomitant treatment with AZD9291 80 mg once daily and rifampicin 600 mg once daily on Days 29 to 49 (Part A). All treatments (AZD9291 and rifampicin) were administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 49. |
| Measure Participants | 32 |
| Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL] |
58610
(36.8)
|
| Title | Assessment of Tss,Max for AZD9291, and AZ5104 and AZ7550 (Metabolites) |
|---|---|
| Description | Rate and extent of absorption of AZD9291, and AZ5104 and AZ7550 (metabolites) by assessment of time to reach maximum plasma concentration at steady state (tss,max). AZD9291 dosing alone and in combination with rifampicin (all periods). |
| Time Frame | Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A. |
Outcome Measure Data
| Analysis Population Description |
|---|
| The PK analysis set included all dosed patients who had at least 1 quantifiable plasma concentration collected post-dose without any important deviations or events that would exclude the patient. |
| Arm/Group Title | AZD9291 Alone (Period 1) | AZD9291 + Rifampicin (Period 2) | AZD9291 Alone (Period 3) |
|---|---|---|---|
| Arm/Group Description | AZD9291 80 mg once daily on Days 1 to 28 (Part A). AZD9291 was administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 28. | Concomitant treatment with AZD9291 80 mg once daily and rifampicin 600 mg once daily on Days 29 to 49 (Part A). All treatments (AZD9291 and rifampicin) were administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 49. | AZD9291 80 mg once daily on Days 50 to 77 (Part A). AZD9291 was administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 77. |
| Measure Participants | 38 | 32 | 28 |
| AZD9291 tss,max |
4.97
|
5.88
|
6.00
|
| AZ5104 tss,max |
6.00
|
6.03
|
6.00
|
| AZ7550 tss,max |
6.14
|
7.95
|
7.03
|
| Title | Assessment of Tss,Max for Rifampicin |
|---|---|
| Description | Rate and extent of absorption of rifampicin by assessment of tss,max. AZD9291 dosing in combination with rifampicin (Period 2). |
| Time Frame | Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A. |
Outcome Measure Data
| Analysis Population Description |
|---|
| The PK analysis set included all dosed patients who had at least 1 quantifiable plasma concentration collected post-dose without any important deviations or events that would exclude the patient. |
| Arm/Group Title | AZD9291 + Rifampicin (Period 2) |
|---|---|
| Arm/Group Description | Concomitant treatment with AZD9291 80 mg once daily and rifampicin 600 mg once daily on Days 29 to 49 (Part A). All treatments (AZD9291 and rifampicin) were administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 49. |
| Measure Participants | 32 |
| Median (Full Range) [h] |
2.00
|
| Title | Assessment of Css,Min for AZD9291, and AZ5104 and AZ7550 (Metabolites) |
|---|---|
| Description | Rate and extent of absorption of AZD9291, and AZ5104 and AZ7550 (metabolites) by assessment of minimum plasma concentration at steady state (Css,min). AZD9291 dosing alone and in combination with rifampicin (all periods). |
| Time Frame | Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A. |
Outcome Measure Data
| Analysis Population Description |
|---|
| The PK analysis set included all dosed patients who had at least 1 quantifiable plasma concentration collected post-dose without any important deviations or events that would exclude the patient. |
| Arm/Group Title | AZD9291 Alone (Period 1) | AZD9291 + Rifampicin (Period 2) | AZD9291 Alone (Period 3) |
|---|---|---|---|
| Arm/Group Description | AZD9291 80 mg once daily on Days 1 to 28 (Part A). AZD9291 was administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 28. | Concomitant treatment with AZD9291 80 mg once daily and rifampicin 600 mg once daily on Days 29 to 49 (Part A). All treatments (AZD9291 and rifampicin) were administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 49. | AZD9291 80 mg once daily on Days 50 to 77 (Part A). AZD9291 was administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 77. |
| Measure Participants | 38 | 31 | 28 |
| AZD9291 Css,min |
354.7
(52.4)
|
50.56
(47.9)
|
326.9
(41.1)
|
| AZ5104 Css,min |
41.80
(62.1)
|
5.816
(51.6)
|
35.37
(51.4)
|
| AZ7550 Css,min |
37.99
(44.0)
|
44.89
(26.9)
|
37.68
(35.4)
|
| Title | Assessment of Css,Min for Rifampicin |
|---|---|
| Description | Rate and extent of absorption of rifampicin by assessment of minimum plasma concentration at steady state (Css,min). AZD9291 dosing in combination with rifampicin (Period 2). |
| Time Frame | Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A. |
Outcome Measure Data
| Analysis Population Description |
|---|
| The PK analysis set included all dosed patients who had at least 1 quantifiable plasma concentration collected post-dose without any important deviations or events that would exclude the patient. |
| Arm/Group Title | AZD9291 + Rifampicin (Period 2) |
|---|---|
| Arm/Group Description | Concomitant treatment with AZD9291 80 mg once daily and rifampicin 600 mg once daily on Days 29 to 49 (Part A). All treatments (AZD9291 and rifampicin) were administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 49. |
| Measure Participants | 32 |
| Geometric Mean (Geometric Coefficient of Variation) [ng/mL] |
NA
(NA)
|
| Title | Assessment of CLss/F for AZD9291 |
|---|---|
| Description | Rate and extent of absorption of AZD9291 by assessment of the apparent plasma clearance following oral administration and multiple dosing (CLss/F). AZD9291 dosing alone and in combination with rifampicin (all periods). |
| Time Frame | Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A. |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | AZD9291 Alone (Period 1) | AZD9291 + Rifampicin (Period 2) | AZD9291 Alone (Period 3) |
|---|---|---|---|
| Arm/Group Description | AZD9291 80 mg once daily on Days 1 to 28 (Part A). AZD9291 was administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 28. | Concomitant treatment with AZD9291 80 mg once daily and rifampicin 600 mg once daily on Days 29 to 49 (Part A). All treatments (AZD9291 and rifampicin) were administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 49. | AZD9291 80 mg once daily on Days 50 to 77 (Part A). AZD9291 was administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 77. |
| Measure Participants | 38 | 32 | 28 |
| Geometric Mean (Geometric Coefficient of Variation) [Litre per hour (L/h)] |
14.74
(44.2)
|
73.07
(43.8)
|
15.92
(36.7)
|
| Title | Assessment of CLss/F for Rifampicin |
|---|---|
| Description | Rate and extent of absorption of rifampicin by assessment of CLss/F. AZD9291 dosing in combination with rifampicin (Period 2). |
| Time Frame | Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A. |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | AZD9291 + Rifampicin (Period 2) |
|---|---|
| Arm/Group Description | Concomitant treatment with AZD9291 80 mg once daily and rifampicin 600 mg once daily on Days 29 to 49 (Part A). All treatments (AZD9291 and rifampicin) were administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 49. |
| Measure Participants | 32 |
| Geometric Mean (Geometric Coefficient of Variation) [L/h] |
10.23
(36.7)
|
| Title | Assessment of the Metabolic Ratios of Css,Max for AZ5104 and AZ7550 (MRCss,Max) |
|---|---|
| Description | Assessment of the metabolite to parent ratio (calculated as AZ5104 to AZD9291 and AZ7550 to AZD9291) for Css,max (MRCss,max). AZD9291 dosing alone and in combination with rifampicin (all periods). |
| Time Frame | Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A. |
Outcome Measure Data
| Analysis Population Description |
|---|
| The PK analysis set included all dosed patients who had at least 1 quantifiable plasma concentration collected post-dose without any important deviations or events that would exclude the patient. |
| Arm/Group Title | AZD9291 Alone (Period 1) | AZD9291 + Rifampicin (Period 2) | AZD9291 Alone (Period 3) |
|---|---|---|---|
| Arm/Group Description | AZD9291 80 mg once daily on Days 1 to 28 (Part A). AZD9291 was administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 28. | Concomitant treatment with AZD9291 80 mg once daily and rifampicin 600 mg once daily on Days 29 to 49 (Part A). All treatments (AZD9291 and rifampicin) were administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 49. | AZD9291 80 mg once daily on Days 50 to 77 (Part A). AZD9291 was administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 77. |
| Measure Participants | 38 | 32 | 28 |
| AZ5104 Css,max / AZD9291 Css,max |
0.1046
(31.0)
|
0.08327
(27.4)
|
0.09544
(27.4)
|
| AZ7550 Css,max / AZD9291 Css,max |
0.09276
(49.3)
|
0.4960
(33.1)
|
0.1002
(38.1)
|
| Title | Assessment of the Metabolic Ratios of AUCtau for AZ5104 and AZ7550 (MRAUCtau) |
|---|---|
| Description | Assessment of the metabolite to parent ratio (calculated as AZ5104 to AZD9291 and AZ7550 to AZD9291) for AUCtau (MRAUCtau). AZD9291 dosing alone and in combination with rifampicin (all periods). |
| Time Frame | Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A. |
Outcome Measure Data
| Analysis Population Description |
|---|
| The PK analysis set included all dosed patients who had at least 1 quantifiable plasma concentration collected post-dose without any important deviations or events that would exclude the patient. |
| Arm/Group Title | AZD9291 Alone (Period 1) | AZD9291 + Rifampicin (Period 2) | AZD9291 Alone (Period 3) |
|---|---|---|---|
| Arm/Group Description | AZD9291 80 mg once daily on Days 1 to 28 (Part A). AZD9291 was administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 28. | Concomitant treatment with AZD9291 80 mg once daily and rifampicin 600 mg once daily on Days 29 to 49 (Part A). All treatments (AZD9291 and rifampicin) were administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 49. | AZD9291 80 mg once daily on Days 50 to 77 (Part A). AZD9291 was administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 77. |
| Measure Participants | 38 | 32 | 28 |
| AZ5104 AUCtau / AZD9291 AUCtau |
0.1109
(29.0)
|
0.09595
(23.6)
|
0.1023
(28.5)
|
| AZ7550 AUCtau / AZD9291 AUCtau |
0.1019
(52.3)
|
0.6459
(28.2)
|
0.1104
(38.8)
|
Adverse Events
| Time Frame | Approximately 3 months for Part A; up to approximately 14 months for Part B and approximately 17 months for Overall (Parts A and B combined). | |||||
|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 77), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP). | |||||
| Arm/Group Title | Overall | Part A | Part B | |||
| Arm/Group Description | Parts A and B of the study combined. | In Part A of the study, each patient received 80 mg oral doses of AZD9291 tablets once daily for 77 days (Days 1 to 77) and additionally received 600 mg oral doses of rifampicin once daily on Days 29 to 49. | In Part B of the study, each patient received 80 mg oral AZD9291 tablet formulation once daily, for the duration of their participation. | |||
All Cause Mortality |
||||||
| Overall | Part A | Part B | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | / (NaN) | |||
Serious Adverse Events |
||||||
| Overall | Part A | Part B | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 11/41 (26.8%) | 7/41 (17.1%) | 6/34 (17.6%) | |||
| Cardiac disorders | ||||||
| Atrial fibrillation | 1/41 (2.4%) | 1 | 0/41 (0%) | 0 | 1/34 (2.9%) | 1 |
| Cardiac failure congestive | 1/41 (2.4%) | 1 | 1/41 (2.4%) | 1 | 0/34 (0%) | 0 |
| Gastrointestinal disorders | ||||||
| Ileus | 1/41 (2.4%) | 1 | 0/41 (0%) | 0 | 1/34 (2.9%) | 1 |
| General disorders | ||||||
| Malaise | 1/41 (2.4%) | 1 | 1/41 (2.4%) | 1 | 0/34 (0%) | 0 |
| Infections and infestations | ||||||
| Influenza | 2/41 (4.9%) | 2 | 1/41 (2.4%) | 1 | 1/34 (2.9%) | 1 |
| Hepatitis B | 1/41 (2.4%) | 1 | 0/41 (0%) | 0 | 1/34 (2.9%) | 1 |
| Pneumonia | 1/41 (2.4%) | 1 | 0/41 (0%) | 0 | 1/34 (2.9%) | 1 |
| Pulmonary sepsis | 1/41 (2.4%) | 1 | 0/41 (0%) | 0 | 1/34 (2.9%) | 1 |
| Injury, poisoning and procedural complications | ||||||
| Femur fracture | 1/41 (2.4%) | 1 | 1/41 (2.4%) | 1 | 0/34 (0%) | 0 |
| Metabolism and nutrition disorders | ||||||
| Hyperkalaemia | 1/41 (2.4%) | 1 | 1/41 (2.4%) | 1 | 0/34 (0%) | 0 |
| Musculoskeletal and connective tissue disorders | ||||||
| Muscular weakness | 1/41 (2.4%) | 1 | 1/41 (2.4%) | 1 | 0/34 (0%) | 0 |
| Nervous system disorders | ||||||
| Thrombotic stroke | 1/41 (2.4%) | 1 | 0/41 (0%) | 0 | 1/34 (2.9%) | 1 |
| Vascular disorders | ||||||
| Thrombophlebitis | 1/41 (2.4%) | 1 | 1/41 (2.4%) | 1 | 0/34 (0%) | 0 |
Other (Not Including Serious) Adverse Events |
||||||
| Overall | Part A | Part B | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 40/41 (97.6%) | 39/41 (95.1%) | 34/34 (100%) | |||
| Blood and lymphatic system disorders | ||||||
| Anaemia | 6/41 (14.6%) | 6 | 3/41 (7.3%) | 3 | 3/34 (8.8%) | 3 |
| Neutropenia | 3/41 (7.3%) | 5 | 2/41 (4.9%) | 2 | 2/34 (5.9%) | 3 |
| Eye disorders | ||||||
| Eye pruritus | 2/41 (4.9%) | 2 | 0/41 (0%) | 0 | 2/34 (5.9%) | 2 |
| Dry eye | 4/41 (9.8%) | 5 | 3/41 (7.3%) | 3 | 2/34 (5.9%) | 2 |
| Gastrointestinal disorders | ||||||
| Constipation | 7/41 (17.1%) | 10 | 4/41 (9.8%) | 4 | 5/34 (14.7%) | 6 |
| Diarrhoea | 22/41 (53.7%) | 39 | 14/41 (34.1%) | 18 | 14/34 (41.2%) | 21 |
| Abdominal pain | 5/41 (12.2%) | 6 | 2/41 (4.9%) | 2 | 3/34 (8.8%) | 4 |
| Abdominal pain upper | 2/41 (4.9%) | 2 | 0/41 (0%) | 0 | 2/34 (5.9%) | 2 |
| Dyspepsia | 3/41 (7.3%) | 3 | 2/41 (4.9%) | 2 | 1/34 (2.9%) | 1 |
| Nausea | 13/41 (31.7%) | 24 | 8/41 (19.5%) | 14 | 9/34 (26.5%) | 10 |
| Stomatitis | 10/41 (24.4%) | 14 | 6/41 (14.6%) | 6 | 6/34 (17.6%) | 8 |
| Vomiting | 11/41 (26.8%) | 16 | 5/41 (12.2%) | 7 | 7/34 (20.6%) | 9 |
| General disorders | ||||||
| Oedema peripheral | 7/41 (17.1%) | 7 | 4/41 (9.8%) | 4 | 3/34 (8.8%) | 3 |
| Asthenia | 7/41 (17.1%) | 8 | 4/41 (9.8%) | 5 | 3/34 (8.8%) | 3 |
| Face oedema | 3/41 (7.3%) | 3 | 2/41 (4.9%) | 2 | 1/34 (2.9%) | 1 |
| Fatigue | 13/41 (31.7%) | 14 | 8/41 (19.5%) | 9 | 5/34 (14.7%) | 5 |
| Non-cardiac chest pain | 3/41 (7.3%) | 3 | 1/41 (2.4%) | 1 | 2/34 (5.9%) | 2 |
| Pyrexia | 5/41 (12.2%) | 6 | 1/41 (2.4%) | 1 | 4/34 (11.8%) | 5 |
| Infections and infestations | ||||||
| Upper respiratory tract infection | 6/41 (14.6%) | 6 | 4/41 (9.8%) | 4 | 2/34 (5.9%) | 2 |
| Folliculitis | 2/41 (4.9%) | 2 | 0/41 (0%) | 0 | 2/34 (5.9%) | 2 |
| Influenza | 2/41 (4.9%) | 2 | 0/41 (0%) | 0 | 2/34 (5.9%) | 2 |
| Lower respiratory tract infection | 3/41 (7.3%) | 3 | 2/41 (4.9%) | 2 | 1/34 (2.9%) | 1 |
| Paronychia | 8/41 (19.5%) | 13 | 2/41 (4.9%) | 2 | 6/34 (17.6%) | 11 |
| Urinary tract infection | 6/41 (14.6%) | 12 | 6/41 (14.6%) | 6 | 2/34 (5.9%) | 6 |
| Investigations | ||||||
| Weight decreased | 7/41 (17.1%) | 7 | 3/41 (7.3%) | 3 | 4/34 (11.8%) | 4 |
| Alanine aminotransferase increased | 3/41 (7.3%) | 4 | 1/41 (2.4%) | 1 | 2/34 (5.9%) | 3 |
| Blood creatinine increased | 3/41 (7.3%) | 4 | 1/41 (2.4%) | 1 | 2/34 (5.9%) | 3 |
| Electrocardiogram QT prolonged | 3/41 (7.3%) | 3 | 0/41 (0%) | 0 | 3/34 (8.8%) | 3 |
| Neutrophil count decreased | 3/41 (7.3%) | 6 | 2/41 (4.9%) | 3 | 2/34 (5.9%) | 3 |
| Platelet count decreased | 5/41 (12.2%) | 7 | 2/41 (4.9%) | 3 | 4/34 (11.8%) | 4 |
| Metabolism and nutrition disorders | ||||||
| Decreased appetite | 19/41 (46.3%) | 22 | 6/41 (14.6%) | 8 | 13/34 (38.2%) | 14 |
| Iron deficiency | 2/41 (4.9%) | 2 | 0/41 (0%) | 0 | 2/34 (5.9%) | 2 |
| Hyperkalaemia | 3/41 (7.3%) | 3 | 2/41 (4.9%) | 2 | 1/34 (2.9%) | 1 |
| Hypokalaemia | 2/41 (4.9%) | 2 | 0/41 (0%) | 0 | 2/34 (5.9%) | 2 |
| Musculoskeletal and connective tissue disorders | ||||||
| Arthralgia | 5/41 (12.2%) | 6 | 3/41 (7.3%) | 3 | 3/34 (8.8%) | 3 |
| Back pain | 11/41 (26.8%) | 17 | 6/41 (14.6%) | 8 | 5/34 (14.7%) | 9 |
| Muscle spasms | 2/41 (4.9%) | 2 | 0/41 (0%) | 0 | 2/34 (5.9%) | 2 |
| Musculoskeletal chest pain | 2/41 (4.9%) | 2 | 0/41 (0%) | 0 | 2/34 (5.9%) | 2 |
| Musculoskeletal pain | 9/41 (22%) | 11 | 4/41 (9.8%) | 6 | 5/34 (14.7%) | 5 |
| Myalgia | 3/41 (7.3%) | 3 | 1/41 (2.4%) | 1 | 2/34 (5.9%) | 2 |
| Pain in extremity | 4/41 (9.8%) | 5 | 2/41 (4.9%) | 3 | 2/34 (5.9%) | 2 |
| Nervous system disorders | ||||||
| Dizziness | 3/41 (7.3%) | 3 | 0/41 (0%) | 0 | 3/34 (8.8%) | 3 |
| Headache | 8/41 (19.5%) | 13 | 7/41 (17.1%) | 10 | 2/34 (5.9%) | 3 |
| Psychiatric disorders | ||||||
| Insomnia | 3/41 (7.3%) | 3 | 2/41 (4.9%) | 2 | 1/34 (2.9%) | 1 |
| Renal and urinary disorders | ||||||
| Haematuria | 3/41 (7.3%) | 3 | 2/41 (4.9%) | 2 | 1/34 (2.9%) | 1 |
| Pollakiuria | 3/41 (7.3%) | 3 | 3/41 (7.3%) | 3 | 0/34 (0%) | 0 |
| Respiratory, thoracic and mediastinal disorders | ||||||
| Cough | 10/41 (24.4%) | 12 | 7/41 (17.1%) | 7 | 4/34 (11.8%) | 5 |
| Dyspnoea | 5/41 (12.2%) | 7 | 3/41 (7.3%) | 4 | 2/34 (5.9%) | 3 |
| Oropharyngeal pain | 4/41 (9.8%) | 4 | 3/41 (7.3%) | 3 | 1/34 (2.9%) | 1 |
| Skin and subcutaneous tissue disorders | ||||||
| Alopecia | 2/41 (4.9%) | 2 | 0/41 (0%) | 0 | 2/34 (5.9%) | 2 |
| Dermatitis acneiform | 3/41 (7.3%) | 3 | 2/41 (4.9%) | 2 | 1/34 (2.9%) | 1 |
| Dry skin | 17/41 (41.5%) | 27 | 10/41 (24.4%) | 12 | 12/34 (35.3%) | 15 |
| Nail discolouration | 2/41 (4.9%) | 2 | 0/41 (0%) | 0 | 2/34 (5.9%) | 2 |
| Pruritus | 6/41 (14.6%) | 8 | 4/41 (9.8%) | 4 | 4/34 (11.8%) | 4 |
| Rash maculo-papular | 3/41 (7.3%) | 3 | 3/41 (7.3%) | 3 | 0/34 (0%) | 0 |
| Skin fissures | 4/41 (9.8%) | 7 | 4/41 (9.8%) | 4 | 1/34 (2.9%) | 3 |
| Vascular disorders | ||||||
| Hypotension | 3/41 (7.3%) | 3 | 0/41 (0%) | 0 | 3/34 (8.8%) | 3 |
Limitations/Caveats
At end of Part B, the CAP allowed patients to continue receiving AZD9291 if still deriving clinical benefit. No clinical data was databased during the CAP; thus AE data is presented to end of Part B only.
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
The Principal Investigator (PI) agrees to collaborate on the contents and formation of any publication and to pay due consideration to comments and opinions offered. AstraZeneca have 30 days for final manuscript review and may require that submission for publication be delayed in order to file patent application.
Results Point of Contact
| Name/Title | Dr Karen So |
|---|---|
| Organization | AstraZeneca |
| Phone | |
| ClinicalTrialTransparency@astrazeneca.com |
Responsible Party:
AstraZeneca
ClinicalTrials.gov Identifier:
NCT02197247
Other Study ID Numbers:
- D5160C00013
- 2014-001525-32
First Posted:
Jul 22, 2014
Last Update Posted:
Jul 12, 2021
Last Verified:
Jun 1, 2021