A Study in Healthy Smokers to Investigate the Effect of Food on the Bioavailability of Cytisine in a New Formulation

• Sponsor: Achieve Life Sciences (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03509948
• Collaborator: (none)
• Enrollment: 13
• Location: 1
• Arms: 2
• Actual Duration (Months): 1.5
• Patients Per Site Per Month: 8.6

Study Details

Study Description

Brief Summary

This will be an open-label, randomised, 2-treatment period, single-dose crossover study to determine the comparative bioavailability and renal elimination following single-dose administration of 3.0 mg cytisine in healthy smokers under fed and fasted conditions.

Condition or Disease	Intervention/Treatment	Phase
Smoking Cessation	Drug: cytisine	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 13 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1 Open Label, Randomized, Two-Way Crossover Study in Healthy Smokers to Investigate the Effect of Food on the Bioavailability of Cytisine in a New Formulation
• Actual Study Start Date: Apr 27, 2018
• Actual Primary Completion Date: Jun 10, 2018
• Actual Study Completion Date: Jun 12, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Schedule A: Fed Then Fasted Schedule A (6 participants): Period 1: cytisine (2 x 1.5 mg tablets) will be administered 30 minutes after the start of a high fat breakfast (fed state) Period 2: cytisine (2 x 1.5 mg tablets) will be administered after an overnight fast of at least 10 hours (fasting state)	Drug: cytisine; cytisine 1.5 mg film-coated tablets; Other Names: Tabex
Experimental: Schedule B: Fasted Then Fed Schedule B (6 participants): Period 1: cytisine (2 x 1.5 mg tablets) will be administered after an overnight fast of at least 10 hours (fasting state) Period 2: cytisine (2 x 1.5 mg tablets) will be administered 30 minutes after the start of a high fat breakfast (fed state)	Drug: cytisine; cytisine 1.5 mg film-coated tablets; Other Names: Tabex

Outcome Measures

Primary Outcome Measures

1. Maximum Concentration (Cmax) [Pre-dose (within 60 minutes prior to dosing), up to 48 hours post-dose on Days 1-5]

2. Area Under the Concentration Versus Time Curve (AUC) Extrapolated to Infinity (AUC0-∞) [Pre-dose (within 60 minutes prior to dosing) up to 48 hours post dose on Days 1-5]

3. Total Cytisine Excreted in Urine Over 48 Hours (Ae0-48h) [Pre-dose (within 60 minutes prior to dosing) up to 48 hours post dose on Days 1-5]

4. Percent of Total Cytisine Excreted in Urine Over 48 Hours (Ae0-48h%) [Pre-dose (within 60 minutes prior to dosing) up to 48 hours post dose on Days 1-5]

Secondary Outcome Measures

1. Time to Cmax (Tmax) [Pre-dose (within 60 minutes prior to dosing) up to 48 hours post dose on Days 1-5]

2. Terminal Elimination Half-Life (T1/2) [Pre-dose (within 60 minutes prior to dosing) up to 48 hours post dose on Days 1-5]

3. AUC From Time of Dosing to Last Measurable Concentration (AUC0-t) [Pre-dose (within 60 minutes prior to dosing) up to 48 hours post dose on Days 1-5]

4. Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Withdrawal of Study Drug [Baseline (Day 0) through Day 5 plus 6-8 days]

   An adverse event (AE) is defined as any untoward medical occurrence in a clinical trial participant administered a medicinal product and which does not necessarily have a causal relationship with the treatment. A serious adverse event (SAE) is defined as an AE that: results in death; is life-threatening; requires hospitalization or prolongs existing inpatient hospitalization; results in persistent or significant disability or incapacity; results in a congenital abnormality or birth defect; is an important medical event which requires medical intervention to prevent any of the above outcomes. TEAEs are defined as AEs not present prior to first administration of investigational product, or AEs present before first administration of investigational product that worsen after the participant receives the first dose of investigational product. Relationship of the TEAE to study drug was evaluated as: definite, probably, possible, unlikely, or not related.

5. Number of Participants With Clinically Significant Biochemistry, Hematology, Urinalysis, and/or 12-lead Electrocardiogram (ECG) Values [Screening through Day 5]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

To be Confirmed at Screening

1. Subject is current cigarette smoker.

2. Healthy males and females between 18 and 55 years of age.

3. If a female subject of child bearing potential, a negative pregnancy test at screening and admission and willing to use an effective method of contraception (unless of non-childbearing potential or where abstaining from sexual intercourse is in line with the preferred and usual lifestyle of the subject) from first dose until 3 months after last dose of cytisine.

4. If a female subject of non-child bearing potential, a negative pregnancy test at screening and admission. For the purposes of this study, this is defined as the subject being amenorrheic for at least 12 consecutive months or at least 4 months post-surgical sterilisation (including bilateral fallopian tube ligation or bilateral oophorectomy with or without hysterectomy). Menopausal status will be confirmed by demonstrating at screening that levels of follicle stimulating hormone (FSH) fall within the respective pathology reference range. In the event a subject's menopause status has been clearly established (for example, the subject indicates she has been amenorrheic for 10 years), but FSH levels are not consistent with a post-menopausal condition, determination of subject eligibility will be at Investigator's discretion following consultation with the Sponsor.

5. If a male subject, willing to use an effective method of contraception (unless anatomically sterile or where abstaining from sexual intercourse is in line with the preferred and usual lifestyle of the subject) from first dose until 3 months after last dose of cytisine.

6. Subject with a body mass index (BMI) of 23-28 kg/m^{2. BMI = body weight in kg / [height in m}2].

7. Subject with no clinically significant abnormal serum biochemistry or haematology values within 28 days before the first dose of cytisine.

8. Subject with negative urinary drugs of abuse screen, determined within 28 days before the first dose of cytisine (a positive result may be repeated at Investigator's discretion).

9. Subject with negative human immunodeficiency virus (HIV), hepatitis B surface antigen (Hep B) and hepatitis C virus antibody (Hep C) results.

10. Subject with no clinically significant abnormalities in 12-lead ECG determined after minimum of 5 minutes in supine position within 28 days before the first dose of cytisine.

11. Subject with no clinically significant abnormalities in vital signs (systolic blood pressure between 90-140 mmHg, diastolic blood pressure (DBP) between 50 and 90 mmHg, and pulse rate (PR) between 40-100 bpm, measured on the dominant arm after minimum of 5 minutes in supine position) determined within 28 days before first dose of cytisine.

12. Subject must be available to complete the study (including post study follow-up) and comply with study restrictions.

13. Subject must provide written informed consent to participate in the study.

To be Re-Confirmed Prior to Dosing

1. Subject continues to meet all screening inclusion criteria (before the cytisine dose).

2. Subject has a negative urinary drugs of abuse screen (including alcohol).

3. Female subject has a negative urine pregnancy test.

Exclusion Criteria:

To be Confirmed at Screening

1. Known hypersensitivity/allergy reaction to varenicline, other cytisine-derivatives or any of the excipients in the Tabex formulation (cellulose, talc, magnesium).

2. History of severe hypersensitivity reactions to any other drugs.

3. History of any medical condition (e.g. gastrointestinal, renal or hepatic) or surgical condition (e.g. cholecystectomy, gastrectomy) that may affect drug pharmacokinetics (absorption, distribution, metabolism or excretion).

4. Female subjects who are breast feeding.

5. Difficulty in donating blood on either arm or known history.

6. History of alcoholism or drug abuse within last 2 years.

7. Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements within 14 days (or 5 half-lives, whichever is longer) prior to the cytisine dose, unless in the opinion of the Investigator the medication will not interfere with the study procedures or compromise subject safety.

8. Participated in any investigational drug clinical trial within the previous 3 months or a marketed drug trial within the previous 30 days prior to randomization on Day 1 of Period 1.

9. Donation of 450 mL or more blood or had history of significant blood loss due to any reason or had plasmapheresis within 3 months before the cytisine dose.

10. Any inability or difficulty in fasting.

11. Inability to communicate well with Investigators (i.e., language problem, poor mental development or impaired cerebral function).

12. Any other condition that the Principal Investigator considers making the subject unsuitable for this study.

To be Re-Confirmed Prior to Dosing:

1. Development of any exclusion criteria since screening.

2. Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements since screening, unless in the opinion of the Investigator the medication will not interfere with the study procedures or compromise subject safety.

3. Participation in a clinical study since the screening visit.

4. Donation of 450 mL or more blood since the screening visit.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Simbec Research Ltd	Cardiff		United Kingdom	CF11 9AB

Sponsors and Collaborators

• Achieve Life Sciences

Investigators

• Principal Investigator: Ezanul Abd Wahab, MD, Simbec Research Ltd (Simbec)

Study Documents (Full-Text)

• Study Protocol - Apr 3, 2018
• Statistical Analysis Plan - Jul 10, 2018

More Information

Publications

None provided.

• Responsible Party: Achieve Life Sciences
• ClinicalTrials.gov Identifier: NCT03509948
• Other Study ID Numbers: ACH-CYT-07
• First Posted: Apr 27, 2018
• Last Update Posted: Sep 24, 2019
• Last Verified: Sep 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Study Results

Participant Flow

Arm/Group Title	3 mg Cytisine, Schedule A: Fed Then Fasted	3 mg Cytisine, Schedule B: Fasted Then Fed
Arm/Group Description	Period 1: Cytisine (2 x 1.5 mg tablets) administered 30 minutes after the start of a high fat breakfast (fed state). Period 2: Cytisine (2 x 1.5 mg tablets) administered after an overnight fast of at least 10 hours (fasting state).	Period 1: Cytisine (2 x 1.5 mg tablets) administered after an overnight fast of at least 10 hours (fasting state). Period 2: Cytisine (2 x 1.5 mg tablets) administered 30 minutes after the start of a high fat breakfast (fed state).
Period Title: Overall Study
STARTED	6	7
COMPLETED	6	6
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	All Study Participants
Arm/Group Description	3 mg Cytisine, Schedule A: Fed Then Fasted Period 1: Cytisine (2 x 1.5 mg tablets) administered 30 minutes after the start of a high fat breakfast (fed state). Period 2: Cytisine (2 x 1.5 mg tablets) administered after an overnight fast of at least 10 hours (fasting state). 3 mg Cytisine, Schedule B: Fasted Then Fed Period 1: Cytisine (2 x 1.5 mg tablets) administered after an overnight fast of at least 10 hours (fasting state). Period 2: Cytisine (2 x 1.5 mg tablets) administered 30 minutes after the start of a high fat breakfast (fed state).
Overall Participants	13
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	33.3 (11.87)
Sex: Female, Male (Count of Participants)
Female	3 23.1%
Male	10 76.9%
Race/Ethnicity, Customized (Count of Participants)
White	13 100%

Outcome Measures

1. Primary Outcome

Title	Maximum Concentration (Cmax)
Time Frame	Pre-dose (within 60 minutes prior to dosing), up to 48 hours post-dose on Days 1-5

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) Set: All randomized participants who received both doses of cytisine and had sufficient, protocol-compliant plasma concentration-time profiles.

Arm/Group Title	3 mg Cytisine: Fed	3 mg Cytisine: Fasted
Arm/Group Description	Cytisine (2 x 1.5 mg tablets) administered 30 minutes after the start of a high fat breakfast (fed state)	Cytisine (2 x 1.5 mg tablets) administered after an overnight fast of at least 10 hours (fasting state)
Measure Participants	12	12
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	26.2 (37.2)	32.9 (23.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	3 mg Cytisine: Fed, 3 mg Cytisine: Fasted
	Comments	Fed/Fasted Ratio
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Least Squares Mean
	Estimated Value	79.57
	Confidence Interval	(2-Sided) 90%; 66.40 to 95.35
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Area Under the Concentration Versus Time Curve (AUC) Extrapolated to Infinity (AUC0-∞)
Time Frame	Pre-dose (within 60 minutes prior to dosing) up to 48 hours post dose on Days 1-5

Outcome Measure Data

Analysis Population Description

PK Set: All randomized participants who received both doses of cytisine and had sufficient, protocol-compliant plasma concentration-time profiles.

Arm/Group Title	3 mg Cytisine: Fed	3 mg Cytisine: Fasted
Arm/Group Description	Cytisine (2 x 1.5 mg tablets) administered 30 minutes after the start of a high fat breakfast (fed state)	Cytisine (2 x 1.5 mg tablets) administered after an overnight fast of at least 10 hours (fasting state)
Measure Participants	12	12
Geometric Mean (Geometric Coefficient of Variation) [h*ng/mL]	165 (17.5)	179 (13.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	3 mg Cytisine: Fed, 3 mg Cytisine: Fasted
	Comments	Fed/Fasted Ratio
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Least Squares Mean
	Estimated Value	92.08
	Confidence Interval	(2-Sided) 90%; 88.37 to 95.95
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Primary Outcome

Title	Total Cytisine Excreted in Urine Over 48 Hours (Ae0-48h)
Time Frame	Pre-dose (within 60 minutes prior to dosing) up to 48 hours post dose on Days 1-5

Outcome Measure Data

Analysis Population Description

Urine Excretion Set: All participants who received both doses of cytisine and had sufficient, protocol-compliant plasma concentration-time profiles.

Arm/Group Title	3 mg Cytisine: Fed	3 mg Cytisine: Fasted
Arm/Group Description	Cytisine (2 x 1.5 mg tablets) administered 30 minutes after the start of a high fat breakfast (fed state)	Cytisine (2 x 1.5 mg tablets) administered after an overnight fast of at least 10 hours (fasting state)
Measure Participants	12	12
Geometric Mean (Geometric Coefficient of Variation) [mg]	2.40 (21.3)	2.64 (15.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	3 mg Cytisine: Fed, 3 mg Cytisine: Fasted
	Comments	Fed/Fasted Ratio
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Least Squares Mean
	Estimated Value	90.89
	Confidence Interval	(2-Sided) 90%; 84.99 to 97.20
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Primary Outcome

Title	Percent of Total Cytisine Excreted in Urine Over 48 Hours (Ae0-48h%)
Time Frame	Pre-dose (within 60 minutes prior to dosing) up to 48 hours post dose on Days 1-5

Outcome Measure Data

Analysis Population Description

Urine Excretion Set: All participants who received both doses of cytisine and had sufficient, protocol-compliant plasma concentration-time profiles.

Arm/Group Title	3 mg Cytisine: Fed	3 mg Cytisine: Fasted
Arm/Group Description	Cytisine (2 x 1.5 mg tablets) administered 30 minutes after the start of a high fat breakfast (fed state)	Cytisine (2 x 1.5 mg tablets) administered after an overnight fast of at least 10 hours (fasting state)
Measure Participants	12	12
Mean (Standard Deviation) [percent of cytisine excreted in urine]	82.60 (17.627)	89.22 (13.777)

5. Secondary Outcome

Title	Time to Cmax (Tmax)
Time Frame	Pre-dose (within 60 minutes prior to dosing) up to 48 hours post dose on Days 1-5

Outcome Measure Data

Analysis Population Description

PK Set: All randomized participants who received both doses of cytisine and had sufficient, protocol-compliant plasma concentration-time profiles.

Arm/Group Title	3 mg Cytisine: Fed	3 mg Cytisine: Fasted
Arm/Group Description	Cytisine (2 x 1.5 mg tablets) administered 30 minutes after the start of a high fat breakfast (fed state)	Cytisine (2 x 1.5 mg tablets) administered after an overnight fast of at least 10 hours (fasting state)
Measure Participants	12	12
Median (Full Range) [hours]	1.50	0.750

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	3 mg Cytisine: Fed, 3 mg Cytisine: Fasted
	Comments	Fed/Fasted Ratio
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Least Squares Mean
	Estimated Value	1.00
	Confidence Interval	(2-Sided) 90%; 0.25 to 1.75
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Terminal Elimination Half-Life (T1/2)
Time Frame	Pre-dose (within 60 minutes prior to dosing) up to 48 hours post dose on Days 1-5

Outcome Measure Data

Analysis Population Description

PK Set: All randomized participants who received both doses of cytisine and had sufficient, protocol-compliant plasma concentration-time profiles.

Arm/Group Title	3 mg Cytisine: Fed	3 mg Cytisine: Fasted
Arm/Group Description	Cytisine (2 x 1.5 mg tablets) administered 30 minutes after the start of a high fat breakfast (fed state)	Cytisine (2 x 1.5 mg tablets) administered after an overnight fast of at least 10 hours (fasting state)
Measure Participants	12	12
Mean (Standard Deviation) [hours]	4.59 (0.566)	4.73 (0.437)

7. Secondary Outcome

Title	AUC From Time of Dosing to Last Measurable Concentration (AUC0-t)
Time Frame	Pre-dose (within 60 minutes prior to dosing) up to 48 hours post dose on Days 1-5

Outcome Measure Data

Analysis Population Description

PK Set: All randomized participants who received both doses of cytisine and had sufficient, protocol-compliant plasma concentration-time profiles.

Arm/Group Title	3 mg Cytisine: Fed	3 mg Cytisine: Fasted
Arm/Group Description	Cytisine (2 x 1.5 mg tablets) administered 30 minutes after the start of a high fat breakfast (fed state)	Cytisine (2 x 1.5 mg tablets) administered after an overnight fast of at least 10 hours (fasting state)
Measure Participants	12	12
Geometric Mean (Geometric Coefficient of Variation) [h*ng/mL]	158 (17.2)	173 (13.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	3 mg Cytisine: Fed, 3 mg Cytisine: Fasted
	Comments	Fed/Fasted Ratio
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Least Squares Mean
	Estimated Value	91.40
	Confidence Interval	(2-Sided) 90%; 87.55 to 95.41
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Withdrawal of Study Drug
Description	An adverse event (AE) is defined as any untoward medical occurrence in a clinical trial participant administered a medicinal product and which does not necessarily have a causal relationship with the treatment. A serious adverse event (SAE) is defined as an AE that: results in death; is life-threatening; requires hospitalization or prolongs existing inpatient hospitalization; results in persistent or significant disability or incapacity; results in a congenital abnormality or birth defect; is an important medical event which requires medical intervention to prevent any of the above outcomes. TEAEs are defined as AEs not present prior to first administration of investigational product, or AEs present before first administration of investigational product that worsen after the participant receives the first dose of investigational product. Relationship of the TEAE to study drug was evaluated as: definite, probably, possible, unlikely, or not related.
Time Frame	Baseline (Day 0) through Day 5 plus 6-8 days

Outcome Measure Data

Analysis Population Description

Safety Set: All randomized participants who received at least 1 dose of cytisine.

Arm/Group Title	3 mg Cytisine: Fed	3 mg Cytisine: Fasted
Arm/Group Description	Cytisine (2 x 1.5 mg tablets) administered 30 minutes after the start of a high fat breakfast (fed state)	Cytisine (2 x 1.5 mg tablets) administered after an overnight fast of at least 10 hours (fasting state)
Measure Participants	12	13
TEAE	2 15.4%	0 NaN
Serious TEAE	0 0%	0 NaN
TEAE Leading to withdrawal of study drug	0 0%	0 NaN
Mild TEAE	2 15.4%	0 NaN
Moderate TEAE	0 0%	0 NaN
Severe TEAE	0 0%	0 NaN
TEAE Relationship: Unlikely	1 7.7%	0 NaN
TEAE Relationship: Not Related	1 7.7%	0 NaN

9. Secondary Outcome

Title	Number of Participants With Clinically Significant Biochemistry, Hematology, Urinalysis, and/or 12-lead Electrocardiogram (ECG) Values
Time Frame	Screening through Day 5

Outcome Measure Data

Analysis Population Description

Safety Set: All randomized participants who received at least 1 dose of cytisine.

Arm/Group Title	3 mg Cytisine: Fed	3 mg Cytisine: Fasted
Arm/Group Description	Cytisine (2 x 1.5 mg tablets) administered 30 minutes after the start of a high fat breakfast (fed state)	Cytisine (2 x 1.5 mg tablets) administered after an overnight fast of at least 10 hours (fasting state)
Measure Participants	12	13
Biochemistry	0 0%	0 NaN
Hematology	0 0%	0 NaN
Urinalysis	0 0%	0 NaN
ECG	0 0%	0 NaN

Adverse Events

Time Frame	Baseline (Day 0) through Day 5 plus 6-8 days
Adverse Event Reporting Description	TEAEs are presented
Arm/Group Title	3 mg Cytisine: Fed		3 mg Cytisine: Fasted
Arm/Group Description	Cytisine (2 x 1.5 mg tablets) administered 30 minutes after the start of a high fat breakfast (fed state)		Cytisine (2 x 1.5 mg tablets) administered after an overnight fast of at least 10 hours (fasting state)
All Cause Mortality
	3 mg Cytisine: Fed		3 mg Cytisine: Fasted
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/13 (0%)
Serious Adverse Events
	3 mg Cytisine: Fed		3 mg Cytisine: Fasted
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/13 (0%)
Other (Not Including Serious) Adverse Events
	3 mg Cytisine: Fed		3 mg Cytisine: Fasted
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/12 (16.7%)		0/13 (0%)
Gastrointestinal disorders
Abdominal distension	1/12 (8.3%)		0/13 (0%)
Nervous system disorders
Headache	1/12 (8.3%)		0/13 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Principal Investigators are bound by requirements outlined in their individual clinical trial agreements with regard to publication of trial results.