My-CRA: Oral Liquid 13-cis-retinoic Acid (13-CRA)

• Sponsor: Nova Laboratories Limited (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03291080
• Collaborator: (none)
• Enrollment: 20
• Locations: 10
• Arms: 2
• Actual Duration (Months): 16.9
• Patients Per Site: 2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

An open label, randomised, multiple dose, cross-over relative bioavailability and pharmacokinetics trial of a novel oral liquid and capsule formulations of 13-CRA administered to patients from 0 months - < 21 years.

Condition or Disease	Intervention/Treatment	Phase
Neuroblastoma	Drug: Liquid 13-Cis Retinoic Acid; Drug: Extracted capsules 13-CRA	Phase 1/Phase 2

Detailed Description

All patients requiring at least two cycles of 13-CRA therapy will be eligible for recruitment into the trial.

13-CRA will be prescribed to patients according to local treatment protocols at each clinical site. The dose administered will be 200mg/m2/day for both test and reference product. Patients with a body weight of ≤12kg will receive a dose of 160 mg/m2/day.

The pharmacokinetics of 13-CRA liquid (test product) and extracted from capsule (reference product) will be evaluated over two months. Prior to the initiation of 13-CRA treatment as part of the trial, patients will be randomised to receive either liquid or capsule formulation in "My-CRA month 1". The patients will then cross-over to the alternative formulation in "My-CRA month 2". The patients on the trial who require further treatment will revert to standard therapy i.e. 13-CRA extracted from capsules according to local practice.

Study Design

• Study Type: Interventional
• Actual Enrollment: 20 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: Relative Bioavailability and Comparative Pharmacokinetics of 13-CRA Oral Liquid and Extracted Capsule Formulations: a Randomised, Open Label, Multi-dose, Cross-over Clinical Trial in Patients Requiring Treatment Cycles of 13-CRA.
• Actual Study Start Date: Apr 17, 2018
• Actual Primary Completion Date: Sep 12, 2019
• Actual Study Completion Date: Sep 12, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Liquid Oral liquid formulation of 13-Cis Retinoic Acid - test product.	Drug: Liquid 13-Cis Retinoic Acid; Liquid 13-Cis Retinoic Acid; Other Names: Isotretinoin
Experimental: Capsule Isotretinoin capsules (13-CRA extracted per standard of care)- reference product.	Drug: Extracted capsules 13-CRA; Extracted capsules 13-CRA; Other Names: Isotretinoin

Outcome Measures

Primary Outcome Measures

1. Relative Bioavailability [On day 1 and 14 of treatment]

   Relative bioavailability (Area under the curve) of 13-CRA administered as oral liquid (test) and extracted capsule (reference) formulations.

Secondary Outcome Measures

1. Maximum Plasma Concentration (Cmax) [On day 1 and 14 of treatment]

   Pharmacokinetic parameter for 13 CRA extracted capsules versus oral liquid formulation

2. Time to Maximum Concentration (Tmax) [On day 1 and 14 of treatment]

   Pharmacokinetic parameter for 13 CRA extracted capsules versus oral liquid formulation

3. Area Under Plasma Concentration Time Curve (AUC) Metabolite [On day 1 and 14 of treatment]

   Pharmacokinetic parameter for 13 CRA extracted capsules versus oral liquid formulation- metabolite 4-oxo-13-cisRA

4. Cmax (ng/mL)- Metabolite [On day 1 and 14 of treatment]

   Pharmacokinetic parameter for metabolite 4-oxo-13-cisRA PK

5. T Max of Metabolite [On day 1 and 14 of treatment]

   T max for metabolite -4-oxo-13-cisRA PK

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 21 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Male or female aged from 0 years to < 21 years of age.

2. Patient with high risk neuroblastoma, or unresectable, unfavourable histology intermediate risk neuroblastoma the latter age ≥ 18 months at diagnosis

3. Patient who is scheduled to receive at least two treatment cycles of 13-CRA.

4. Patient who cannot swallow 13-CRA capsules (i.e. requires extraction of 13-CRA from the capsules).

5. Negative pregnancy test for females of child-bearing potential before initiation of treatment, and sexually active patients and partners agreeing to undertake adequate contraceptive measures (see section 4.5).

6. Provision of a single or double lumen central venous catheter for sampling (i.e. already in place).

7. Parent(s)/legal guardian able and willing to provide written informed consent for the patient to take part in the trial.

8. Where applicable, the patient should assent to undergo blood sampling for pharmacokinetic purposes and to allow physiological measurements to be made.

Exclusion Criteria:

1. Any clinically significant medical condition or abnormality, which, in the opinion of the investigator, might compromise the safety of the patient or which might interfere with the trial.

2. Diagnosis of high-risk neuroblastoma (HRNBL) which is currently being treated on the SIOPEN HRNBL trial (patients who have exited this trial will be eligible).

3. Known allergy to 13-CRA or any of the excipients.

4. Inadequate contraception measures in females of childbearing age.

5. Receiving concomitant treatment with tetracyclines.

Prior to each cycle:

1. Total bilirubin ≤ 1.5 x normal, and (SGPT) ALT ≤ 5 x normal. Veno-occlusive disease if present, should be stable or improving.

2. Skin toxicity no greater than CTCAE Grade 1(10)

3. Serum triglycerides <5.65mmol/L.

4. No haematuria and / or proteinuria on urinalysis.

5. Serum calcium ≤ 2.9mmol/L.

6. Serum creatinine based on age / gender as follows:

Age Maximum Serum Creatinine µmol/L Male Female 1 month to < 6 months 35 35 6 months to < 1 year 44 44 1 to < 2 years 53 53 2 to < 6 years 70 70 6 to < 10 years 88 88 10 to < 13 years 106 106 13 to < 16 years 132 124

≥ 16 years 150 124

1. Patients with a seizure disorder must be well controlled and taking anticonvulsants. CNS toxicity < grade 2 (CTCAE).

Withdrawal Criteria:

1. Positive pregnancy test - pregnancy testing will be undertaken before treatment commences and routinely before each course of treatment in females of childbearing potential. If a patient is found to be pregnant during the trial, the next course of treatment will not be given until the pregnancy has been discussed with the treating clinician, and the patient will be withdrawn from the trial whether or not treatment is continued.

2. Request of the patient, for any reason.

3. Discretion of the investigator.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Bruce Morland	Birmingham		United Kingdom
2	Dr Antony Ng	Bristol		United Kingdom
3	Dr Amos Burke	Cambridge		United Kingdom
4	Mark Brougham	Edinburgh		United Kingdom
5	Dr Martin Elliott	Leeds		United Kingdom
6	Dr Guiseppe Barone	London		United Kingdom
7	Dr Guy Makin	Manchester		United Kingdom
8	Dr Madhumita Dandapani	Nottingham		United Kingdom
9	Kate Wheeler	Oxford		United Kingdom
10	Sucheta Vaidya	Sutton		United Kingdom

Sponsors and Collaborators

• Nova Laboratories Limited

Investigators

• Study Director: Hussain Mulla, PhD, Nova Laboratories Limited

Study Documents (Full-Text)

• Study Protocol - Dec 8, 2017
• Statistical Analysis Plan - Oct 19, 2019

More Information

Publications

None provided.

• Responsible Party: Nova Laboratories Limited
• ClinicalTrials.gov Identifier: NCT03291080
• Other Study ID Numbers: INV500
• First Posted: Sep 25, 2017
• Last Update Posted: Oct 19, 2021
• Last Verified: Sep 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Neuroblastoma; Tretinoin; Isotretinoin

Study Results

Participant Flow

Arm/Group Title	First Oral Liquid, Then Capsule	First Capsule, Then Oral Liquid
Arm/Group Description	Oral liquid formulation of 13-Cis Retinoic Acid (test product) in the first cycle. Then extracted 13-CRA capsule (reference product) in the second cycle.	13-CRA capsules extracted per standard of care (reference product) in the first cycle. Then oral liquid formulation of 13-CRA (test product) in the second cycle.
Period Title: First Cycle (2 Weeks)
STARTED	11	9
COMPLETED	11	9
NOT COMPLETED	0	0
Period Title: First Cycle (2 Weeks)
STARTED	11	9
COMPLETED	11	9
NOT COMPLETED	0	0
Period Title: First Cycle (2 Weeks)
STARTED	9	11
COMPLETED	8	11
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	Liquid First	Extracted Capsule First	Total
Arm/Group Description	Oral liquid formulation of 13-Cis Retinoic Acid (test product) administered in Cycle 1, then 13-CRA extracted capsules (reference product) administered in Cycle 2. The daily dose in each cycle was 200mg per m^2 (in 2 divided doses), reduced to 160 mg per m^2 if weight < 12 kg	13-CRA extracted capsules (reference product) administered in Cycle 1, then oral liquid formulation of 13-Cis Retinoic Acid (test product) administered in Cycle 2. The daily dose in each cycle was 200mg per m^2 (in 2 divided doses), reduced to 160 mg per m^2 if weight < 12 kg	Total of all reporting groups
Overall Participants	11	9	20
Age (Count of Participants)
<=18 years	11 100%	9 100%	20 100%
Between 18 and 65 years	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	4 36.4%	1 11.1%	5 25%
Male	7 63.6%	8 88.9%	15 75%
Race/Ethnicity, Customized (Count of Participants)
White	8 72.7%	7 77.8%	15 75%
Asian or Asian British	2 18.2%	2 22.2%	4 20%
Other	1 9.1%	0 0%	1 5%
Height (Metre) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Metre]	0.974 (0.113)	1.062 (0.21)	1.009 (0.163)
Weight (Kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Kg]	14.66 (3.47)	18.96 (9.09)	16.3 (6.5)

Outcome Measures

1. Primary Outcome

Title	Relative Bioavailability
Description	Relative bioavailability (Area under the curve) of 13-CRA administered as oral liquid (test) and extracted capsule (reference) formulations.
Time Frame	On day 1 and 14 of treatment

Outcome Measure Data

Analysis Population Description

Relative bioavailability - AUC (h.ng/mL)

Arm/Group Title	13-CRA Oral Liquid	13-CRA Extracted Capsule
Arm/Group Description	Oral liquid formulation - test product	Oral liquid formulation - reference product
Measure Participants	20	20
Mean (Standard Deviation) [(h.ng/mL)]	10009.0 (3672.97)	6075.9 (2090.66)

2. Secondary Outcome

Title	Maximum Plasma Concentration (Cmax)
Description	Pharmacokinetic parameter for 13 CRA extracted capsules versus oral liquid formulation
Time Frame	On day 1 and 14 of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	13-CRA Oral Liquid	13-CRA Extracted Capsule
Arm/Group Description	Oral liquid formulation - test product	Extracted Capsules- reference product
Measure Participants	20	20
Mean (Standard Deviation) [(ng/mL)]	1237.6 (662.67)	748.2 (379.28)

3. Secondary Outcome

Title	Time to Maximum Concentration (Tmax)
Description	Pharmacokinetic parameter for 13 CRA extracted capsules versus oral liquid formulation
Time Frame	On day 1 and 14 of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	13-CRA Oral Liquid	13-CRA Extracted Capsule
Arm/Group Description	Oral liquid formulation - test product	Extracted Capsules- reference product
Measure Participants	20	20
Mean (Standard Deviation) [(h)]	3.2 (0.76)	3.0 (0.76)

4. Secondary Outcome

Title	Area Under Plasma Concentration Time Curve (AUC) Metabolite
Description	Pharmacokinetic parameter for 13 CRA extracted capsules versus oral liquid formulation- metabolite 4-oxo-13-cisRA
Time Frame	On day 1 and 14 of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	13-CRA Oral Liquid	13-CRA Extracted Capsule
Arm/Group Description	Oral liquid formulation - test product	Oral liquid formulation - reference product
Measure Participants	20	20
Mean (Standard Deviation) [(h*ng/mL)]	38462.3 (18913.60)	23312.7 (10947.59)

5. Secondary Outcome

Title	Cmax (ng/mL)- Metabolite
Description	Pharmacokinetic parameter for metabolite 4-oxo-13-cisRA PK
Time Frame	On day 1 and 14 of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	13-CRA Oral Liquid	13-CRA Extracted Capsule
Arm/Group Description	Oral liquid formulation - test product	Extracted Capsules- reference product
Measure Participants	20	20
Mean (Standard Deviation) [(ng/mL)]	3366.2 (1648.08)	2039.1 (952.23)

6. Secondary Outcome

Title	T Max of Metabolite
Description	T max for metabolite -4-oxo-13-cisRA PK
Time Frame	On day 1 and 14 of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	13-CRA Oral Liquid	13-CRA Extracted Capsule
Arm/Group Description	Oral liquid formulation - test product	Extracted Capsules- reference product
Measure Participants	20	20
Mean (Standard Deviation) [(h)]	7.1 (1.16)	6.9 (1.16)

Adverse Events

Time Frame	Through study completion, an average of 2 months.
Arm/Group Title	13-CRA Oral Liquid		13-CRA Extracted Capsule
Arm/Group Description	Oral liquid formulation - test product		Oral liquid formulation - reference product
All Cause Mortality
	13-CRA Oral Liquid		13-CRA Extracted Capsule
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/20 (0%)
Serious Adverse Events
	13-CRA Oral Liquid		13-CRA Extracted Capsule
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/20 (50%)		5/20 (25%)
Blood and lymphatic system disorders
Febrile neutropenia	0/20 (0%)	0	2/20 (10%)	2
Gastrointestinal disorders
Haematemesis	1/20 (5%)	1	0/20 (0%)	0
Diarrhoea	1/20 (5%)	1	1/20 (5%)	1
vomiting	1/20 (5%)	1	1/20 (5%)	1
General disorders
Pyrexia	3/20 (15%)	5	2/20 (10%)	3
Immune system disorders
Hypersensitivity	0/20 (0%)	0	1/20 (5%)	1
Infections and infestations
Pharyngitis	1/20 (5%)	1	0/20 (0%)	0
Respiratory syncitial virus infection	0/20 (0%)	0	1/20 (5%)	1
Nervous system disorders
Enteric neuropathy	1/20 (5%)	1	0/20 (0%)	0
Headache	1/20 (5%)	1	0/20 (0%)	0
Renal and urinary disorders
Acute Kidney Injury	1/20 (5%)	1	0/20 (0%)	0
Respiratory, thoracic and mediastinal disorders
Upper respiratory tract infection	1/20 (5%)	1	0/20 (0%)	0
Skin and subcutaneous tissue disorders
Rash	0/20 (0%)	0	1/20 (5%)	1
Other (Not Including Serious) Adverse Events
	13-CRA Oral Liquid		13-CRA Extracted Capsule
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	18/20 (90%)		15/20 (75%)
Blood and lymphatic system disorders
Febrile neutropenia	0/20 (0%)	0	2/20 (10%)	2
Eye disorders
Dry eye	3/20 (15%)	3	2/20 (10%)	2
Gastrointestinal disorders
Chapped Lips	8/20 (40%)	9	6/20 (30%)	6
Constipation	3/20 (15%)	4	3/20 (15%)	3
Diarrhoea	6/20 (30%)	7	5/20 (25%)	6
Vomiting	3/20 (15%)	5	4/20 (20%)	5
General disorders
Pain	2/20 (10%)	2	0/20 (0%)	0
Pyrexia	8/20 (40%)	10	6/20 (30%)	8
Swelling face	0/20 (0%)	0	2/20 (10%)	2
Investigations
Alanine aminotransferase increased	0/20 (0%)	0	2/20 (10%)	2
Platelet count decreased	0/20 (0%)	0	2/20 (10%)	3
Nervous system disorders
Headache	2/20 (10%)	2	0/20 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	0/20 (0%)	0	2/20 (10%)	2
Epistaxis	2/20 (10%)	2	0/20 (0%)	0
Skin and subcutaneous tissue disorders
Dry Skin	8/20 (40%)	8	10/20 (50%)	12
Rash	0/20 (0%)	0	2/20 (10%)	2
Skin exfoliation	7/20 (35%)	7	4/20 (20%)	4
Vascular disorders
Hypotension	0/20 (0%)	0	2/20 (10%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.