A Study to Assess the Efficacy and Safety of Vamorolone in Boys With Duchenne Muscular Dystrophy (DMD)

• Sponsor: ReveraGen BioPharma, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03439670
• Collaborator: European Union (Other), Cooperative International Neuromuscular Research Group (Other), Newcastle University (Other), University of Pittsburgh (Other)
• Enrollment: 121
• Locations: 33
• Arms: 6
• Actual Duration (Months): 38
• Patients Per Site: 3.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Brief Summary: This Phase IIb study is a randomized, double-blind, parallel group, placebo and active-controlled study to evaluate the efficacy, safety, PD, and population PK of vamorolone administered orally at daily doses of 2.0 mg/kg and 6.0 mg/kg versus prednisone 0.75 mg/kg/day and placebo over a Treatment Period of 24 weeks, and to evaluate persistence of effect over a Treatment Period of 48 weeks in ambulant boys ages 4 to <7 years with DMD.

Condition or Disease	Intervention/Treatment	Phase
Duchenne Muscular Dystrophy	Drug: Vamorolone; Drug: Prednisone; Other: Placebo; Drug: Vamorolone; Drug: Prednisone; Other: Placebo; Drug: Vamorolone; Drug: Vamorolone	Phase 2

Detailed Description

This Phase IIb study is a randomized, double-blind, parallel group, placebo and active-controlled study to evaluate the efficacy, safety, PD, and population PK of vamorolone administered orally at daily doses of 2.0 mg/kg and 6.0 mg/kg versus prednisone 0.75 mg/kg/day and placebo over a Treatment Period of 24 weeks, and to evaluate persistence of effect over a Treatment Period of 48 weeks in ambulant boys ages 4 to <7 years with DMD.

The study is comprised of a 5-week Pretreatment Screening Period, a 1-day Pretreatment Baseline Period, a 24-week Treatment Period #1 (Weeks 1-24), a 4-week Transition Period (Weeks 25-28), a 20-week Treatment Period #2 (Weeks 28 + 1 day to 48), and a 4-week Dose-tapering Period (Weeks 49-52).

Subjects will be randomized to one of six treatment groups in a 2:2:1:1:1:1 ratio, where the two prednisone groups in Treatment Period #1 (Groups 3 and 4) will be combined and the two placebo groups in Treatment Period #1 (Groups 5 and 6) will be combined, effectively resulting in a 1:1:1:1 randomization (vamorolone 2.0 mg/kg/day : vamorolone 6.0 mg/kg/day : prednisone 0.75 mg/kg/day : placebo) for Treatment Period #1.

Subjects will be stratified based on age at study entry (<6 vs. ≥ 6 years). During the 4-week Transition Period between Treatment Period #1 and Treatment Period #2, all subjects will continue on the same oral suspension (vamorolone 2.0 mg/kg or 6.0 mg/kg, or matching placebo) they received during Treatment Period #1 and all subjects will have their tablet dose tapered to zero. Thus, subjects randomized to receive vamorolone during Treatment Period #1 (Groups 1 and 2) will continue to receive vamorolone at the same dose, while subjects randomized to receive prednisone will have their dose tapered to zero, and subjects randomized to placebo will continue to receive placebo.

The prednisone group will be used as an active control comparison for safety and efficacy endpoints as requested by the European Medicines Agency (EMA). The placebo group will be used as comparator for efficacy endpoints (superiority model) as requested by the EMA and Food and Drug Administration (FDA) protocol advisory board. Although glucocorticoids are part of the care recommendations for DMD, their adverse effect profile has limited their use. The age at which glucocorticoids should be started in DMD boys is uncertain, ranging from 4 to 7 years, based on a balance between benefits and side effects. In view of the age inclusion criteria and duration of the placebo-controlled study period (6 months), the use of a placebo group has been considered acceptable as in clinical practice it will not cause a real delay in prescription of an accepted treatment for this condition. Any exposure of placebo longer than 6 months was considered unethical.

At the end of the Treatment Period #2, subjects may be given access to vamorolone through an additional study or general access program, or given the option to transition to standard of care treatment for DMD (may include glucocorticoids). Subjects completing VBP15-004 and enrolling directly into an additional vamorolone study or general access program to receive vamorolone will not need to taper their vamorolone dose prior to enrollment. All other subjects will begin a 4-week double-blind Dose-tapering Period during which the dose of study medication will be progressively reduced and discontinued.

Study Design

• Study Type: Interventional
• Actual Enrollment: 121 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase IIb Randomized, Double-blind, Parallel Group, Placebo- and Active-controlled Study With Double-Blind Extension to Assess the Efficacy and Safety of Vamorolone in Ambulant Boys With Duchenne Muscular Dystrophy (DMD)
• Actual Study Start Date: Jun 19, 2018
• Actual Primary Completion Date: Feb 23, 2021
• Actual Study Completion Date: Aug 19, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment Group 1 Patients enrolled in Treatment Group 1 (experimental group) will receive vamorolone 2.0 mg/kg/day for the duration of the study.	Drug: Vamorolone; Oral administration of 2.0 mg/kg/day for the duration of the study.; Other Names: VBP15
Experimental: Treatment Group 2 Patients enrolled in Treatment Group 2 (experimental group) will receive vamorolone at 6.0 mg/kg/day for the duration of the study.	Drug: Vamorolone; Oral administration of 6.0 mg/kg/day for the duration of the study.; Other Names: VBP15
Active Comparator: Treatment Group 3 Patients enrolled in Treatment Group 3 (active comparator group) will receive prednisone 0.75 mg/kg/day for 24 weeks followed by 20 weeks of treatment with 2.0 mg/kg/day vamorolone.	Drug: Prednisone; Oral administration of 0.75 mg/kg/day for 24 weeks.; Drug: Vamorolone; Oral administration of 2.0 mg/kg/day for 20 weeks.; Other Names: VBP15
Active Comparator: Treatment Group 4 Patients enrolled in Treatment Group 4 (active comparator group) will receive prednisone 0.75 mg/kg/day for 24 weeks followed by 20 weeks treatment with 6.0 mg/kg/day vamorolone.	Drug: Prednisone; Oral administration of 0.75 mg/kg/day for 24 weeks.; Drug: Vamorolone; Oral administration of 6.0 mg/kg/day for 20 weeks.; Other Names: VBP15
Placebo Comparator: Treatment Group 5 Patients enrolled in Treatment Group 5 (placebo comparator group) will receive placebo daily for 24 weeks followed by 20 weeks treatment with 2.0 mg/kg/day vamorolone.	Other: Placebo; Oral administration of placebo daily for 24 weeks.; Drug: Vamorolone; Oral administration of 2.0 mg/kg/day for 20 weeks.; Other Names: VBP15
Placebo Comparator: Treatment Group 6 Patients enrolled in Treatment Group 6 (placebo comparator group) will receive placebo daily for 24 weeks followed by 20 weeks treatment with 6.0 mg/kg/day vamorolone.	Other: Placebo; Oral administration of placebo daily for 24 weeks.; Drug: Vamorolone; Oral administration of 6.0 mg/kg/day for 20 weeks.; Other Names: VBP15

Outcome Measures

Primary Outcome Measures

1. Efficacy Measured by Time to Stand Test (TTSTAND) Velocity in Rises/Second Change From Baseline [24 weeks]

   Vamorolone at 6.0mg/kg/day vs. placebo group in change from baseline to the Week 24 assessment

Eligibility Criteria

Criteria

• Ages Eligible for Study: 4 Years to 7 Years
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Subject's parent(s) or legal guardian(s) has (have) provided written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization, where applicable, prior to any study-related procedures; participants will be asked to give written or verbal assent according to local requirements

2. Subject has a centrally confirmed (by TRiNDS central genetic counselor[s]) diagnosis of DMD as defined as:

• Dystrophin immunofluorescence and/or immunoblot showing complete dystrophin deficiency, and clinical picture consistent with typical DMD, OR

• Identifiable mutation within the DMD gene (deletion/duplication of one or more exons), where reading frame can be predicted as 'out-of-frame,' and clinical picture consistent with typical DMD, OR

• Complete dystrophin gene sequencing showing an alteration (point mutation, duplication, other) that is expected to preclude production of the dystrophin protein (i.e., nonsense mutation, deletion/duplication leading to a downstream stop codon), with a clinical picture consistent with typical DMD;

1. Subject is ≥ 4 years and <7 years of age at time of enrollment in the study;

2. Subject weighs >13.0 kg and ≤ 39.9 kg at the Screening Visit;

3. Subject is able to walk independently without assistive devices;

4. Subject is able to complete the Time to Stand Test (TTSTAND) without assistance in <10 seconds, as assessed at the Screening Visit;

5. Clinical laboratory test results are within the normal range at the Screening Visit, or if abnormal, are not clinically significant, in the opinion of the Investigator. [Notes: Serum gamma glutamyl transferase (GGT), creatinine, and total bilirubin all must be ≤ upper limit of the normal range at the Screening Visit. An abnormal vitamin D level that is considered clinically significant will not exclude a subject from randomization];

6. Subject has evidence of chicken pox immunity as determined by:

• Presence of IgG antibodies to varicella, as documented by a positive test result from the local laboratory from blood collected during the Screening Period, OR

• Documentation, provided at the Screening Visit, that the subject has had 2 doses of varicella vaccine, with or without serologic evidence of immunity; the second of the 2 immunizations must have been given at least 14 days prior to randomization.

1. Subject is able to swallow tablets, as confirmed by successful test swallowing of placebo tablets during the Screening Period; and

2. Subject and parent(s)/guardian(s) are willing and able to comply with scheduled visits, study drug administration plan, and study procedures.

Exclusion Criteria:

1. Subject has current or history of major renal or hepatic impairment, diabetes mellitus or immunosuppression;

2. Subject has current or history of chronic systemic fungal or viral infections;

3. Subject has had an acute illness within 4 weeks prior to the first dose of study medication;

4. Subject has used mineralocorticoid receptor agents, such as spironolactone, eplerenone, canrenone (canrenoate potassium), prorenone (prorenoate potassium), mexrenone (mexrenoate potassium) within 4 weeks prior to the first dose of study medication;

5. Subject has a history of primary hyperaldosteronism;

6. Subject has evidence of symptomatic cardiomyopathy [Note: Asymptomatic cardiac abnormality on investigation would not be exclusionary];

7. Subject is currently being treated or has received previous treatment with oral glucocorticoids or other immunosuppressive agents [Notes: Past transient use of oral glucocorticoids or other oral immunosuppressive agents for no longer than 1 month cumulative, with last use at least 3 months prior to first dose of study medication, will be considered for eligibility on a case-by-case basis, unless discontinued for intolerance. Inhaled and/or topical glucocorticoids are permitted if last use is at least 4 weeks prior to first dose of study medication or if administered at stable dose beginning at least 4 weeks prior to first dose of study medication and anticipated to be used at the stable dose regimen for the duration of the study];

8. Subject has an allergy or hypersensitivity to the study medication or to any of its constituents;

9. Subject has used idebenone within 4 weeks prior to the first dose of study medication;

10. Subject has severe behavioral or cognitive problems that preclude participation in the study, in the opinion of the Investigator;

11. Subject has previous or ongoing medical condition, medical history, physical findings or laboratory abnormalities that could affect safety, make it unlikely that treatment and follow-up will be correctly completed or impair the assessment of study results, in the opinion of the Investigator;

12. Subject is taking (or has taken within 4 weeks prior to the first dose of study medication) herbal remedies and supplements which can impact muscle strength and function (e.g., Co-enzyme Q10, creatine, etc);

13. Subject is taking (or has taken within 3 months prior to the first dose of study medication) any medication indicated for DMD, including Exondys51 and Translarna;

14. Subject has been administered a live attenuated vaccine within 14 days prior to the first dose of study medication;

15. Subject is currently taking any other investigational drug or has taken any other investigational drug within 3 months prior to the first dose of study medication;

16. Subject has a sibling who is currently enrolled in any vamorolone study or Expanded Access Program, or who intends to enroll in any vamorolone study or Expanded Access Program during the subject's participation in the VBP15-004 study; or

17. Subject has previously been enrolled in the study. Note: Any parameter/test may be repeated at the Investigator's discretion during Screening to determine reproducibility. In addition, subjects may be rescreened if ineligible due to a transient condition which would prevent the subject from participating, such as an upper respiratory tract infection or injury, or if ineligible due to negative anti-varicella IgG antibody test result.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California Davis	Davis	California	United States	95616
2	University of California Los Angeles	Los Angeles	California	United States	90095
3	Children's Hospital Colorado	Aurora	Colorado	United States	80045
4	Nemours Children's Hospital	Orlando	Florida	United States	32827
5	Ann & Robert H. Lurie Children's Hospital	Chicago	Illinois	United States	60611
6	Gillette Children's Speciality Health Care	Saint Paul	Minnesota	United States	55101
7	Duke Children's Hospital	Durham	North Carolina	United States	27710
8	University of Texas Southwestern Medical Center	Dallas	Texas	United States	75207
9	Children's Hospital of Virginia of Virginia Commonwealth University	Richmond	Virginia	United States	23219
10	Seattle Children's Hospital	Seattle	Washington	United States	98105
11	Royal Children's Hospital	Melbourne		Australia
12	Sydney Children's Hospital	Westmead		Australia
13	Ghent University Hospital	Ghent		Belgium
14	University Hospitals Leuven	Leuven		Belgium
15	Alberta's Children Hospital	Calgary	Alberta	Canada	AB T3B 6A8
16	British Columbia Children's Hospital	Vancouver	British Columbia	Canada	V6H 3N1
17	Children's Hospital of Eastern Ontario	Ottawa	Ontario	Canada	K1H 8L1
18	Montreal Children's Hospital	Montréal	Quebec	Canada	H4A 3J1
19	University Hospital Brno	Brno		Czechia
20	Charles University	Prague		Czechia
21	Agia Sofia Children's Hospital	Athens		Greece
22	Schneider Children's Medical Center	Petah Tikvah		Israel	49202
23	Leiden University Medical Center	Leiden		Netherlands
24	Radboud University	Nijmegen		Netherlands
25	Sant Joan de Deu Hospital - Barcelona, Spain	Barcelona		Spain
26	Hospital Universitario y Politécnico La Fe	Valencia		Spain
27	Queen Silvia Children's Hospital	Gothenburg		Sweden	41685
28	Birmingham Heartlands Hospital	Birmingham		United Kingdom
29	Royal Hospital for Children	Glasgow		United Kingdom	G51 4TF
30	Leeds Teaching Hospital Trust	Leeds		United Kingdom
31	Alder Hey Children's NHS Foundation Trust	Liverpool		United Kingdom	L12 2AP
32	Great Ormond Street Hospital	London		United Kingdom
33	Newcastle upon Tyne Hospitals NHS Foundation Trust	Newcastle upon Tyne		United Kingdom	NE7 7DN

Sponsors and Collaborators

• ReveraGen BioPharma, Inc.
• European Union
• Cooperative International Neuromuscular Research Group
• Newcastle University
• University of Pittsburgh

Investigators

• Study Chair: Michela Guglieri, M.D., John Walton Muscular Dystrophy Research Centre
• Study Chair: Paula Clemens, M.D., University of Pittsburgh

Study Documents (Full-Text)

• Study Protocol - Aug 28, 2020
• Statistical Analysis Plan - May 17, 2021

More Information

Publications

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• Responsible Party: ReveraGen BioPharma, Inc.
• ClinicalTrials.gov Identifier: NCT03439670
• Other Study ID Numbers: VBP15-004
• First Posted: Feb 20, 2018
• Last Update Posted: Jul 13, 2022
• Last Verified: Jun 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by ReveraGen BioPharma, Inc.: Duchenne Muscular Dystrophy; Vamorolone
• Additional relevant MeSH terms: Muscular Dystrophies; Muscular Dystrophy, Duchenne; Prednisone

Study Results

Participant Flow

Arm/Group Title	Treatment Group 1	Treatment Group 2	Treatment Group 3	Treatment Group 4	Treatment Group 5	Treatment Group 6
Arm/Group Description	Patients enrolled in Treatment Group 1 (experimental group) will receive vamorolone 2.0 mg/kg/day for 24 weeks followed by vamorolone 2.0mg/kg/day for 20 weeks.	Patients enrolled in Treatment Group 2 (experimental group) will receive vamorolone 6.0 mg/kg/day for 24 weeks followed by vamorolone 6.0mg/kg/day for 20 weeks.	Patients enrolled in Treatment Group 3 (active comparator group) will receive prednisone 0.75 mg/kg/day for 24 weeks followed by vamorolone 2.0mg/kg/day for 20 weeks.	Patients enrolled in Treatment Group 4 (active comparator group) will receive prednisone 0.75 mg/kg/day for 24 weeks followed by vamorolone 6.0mg/kg/day for 20 weeks.	Patients enrolled in Treatment Group 5 will receive placebo for 24 weeks followed by vamorolone 2mg/kg/day for 20 weeks.	Patients enrolled in Treatment Group 6 will receive placebo for 24 weeks followed by vamorolone 6mg/kg/day for 20 weeks.
Period Title: Overall Study
STARTED	30	30	15	16	15	15
COMPLETED	28	26	15	15	14	14
NOT COMPLETED	2	4	0	1	1	1

Baseline Characteristics

Arm/Group Title	Treatment Group 1	Treatment Group 2	Treatment Group 3	Treatment Group 4	Treatment Group 5	Treatment Group 6	Total
Arm/Group Description	Patients enrolled in Treatment Group 1 (experimental group) will receive vamorolone 2.0 mg/kg/day for 24 weeks followed by vamorolone 2.0mg/kg/day for 20 weeks.	Patients enrolled in Treatment Group 2 (experimental group) will receive vamorolone 6.0 mg/kg/day for 24 weeks followed by vamorolone 6.0mg/kg/day for 20 weeks.	Patients enrolled in Treatment Group 3 (active comparator group) will receive prednisone 0.75 mg/kg/day for 24 weeks followed by vamorolone 2.0mg/kg/day for 20 weeks.	Patients enrolled in Treatment Group 4 (active comparator group) will receive prednisone 0.75 mg/kg/day for 24 weeks followed by vamorolone 6.0mg/kg/day for 20 weeks.	Patients enrolled in Treatment Group 5 will receive placebo for 24 weeks followed by vamorolone 2mg/kg/day for 20 weeks.	Patients enrolled in Treatment Group 6 will receive placebo for 24 weeks followed by vamorolone 6mg/kg/day for 20 weeks.	Total of all reporting groups
Overall Participants	28	28	15	15	14	14	114
Age (Count of Participants)
<=18 years	28 100%	28 100%	15 100%	15 100%	14 100%	14 100%	114 100%
Between 18 and 65 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Male	28 100%	28 100%	15 100%	15 100%	14 100%	14 100%	114 100%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	1 6.7%	0 0%	0 0%	1 0.9%
Asian	4 14.3%	3 10.7%	2 13.3%	1 6.7%	1 7.1%	1 7.1%	12 10.5%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	1 3.6%	1 3.6%	0 0%	0 0%	0 0%	0 0%	2 1.8%
White	23 82.1%	23 82.1%	12 80%	12 80%	11 78.6%	13 92.9%	94 82.5%
More than one race	0 0%	1 3.6%	1 6.7%	1 6.7%	1 7.1%	0 0%	4 3.5%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	1 7.1%	0 0%	1 0.9%
TTSTAND (seconds) (Seconds) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Seconds]	6.01 (2.406)	5.97 (1.991)	5.36 (1.948)	4.53 (0.808)	5.51 (1.578)	5.58 (2.288)	5.560 (1.9498)

Outcome Measures

1. Primary Outcome

Title	Efficacy Measured by Time to Stand Test (TTSTAND) Velocity in Rises/Second Change From Baseline
Description	Vamorolone at 6.0mg/kg/day vs. placebo group in change from baseline to the Week 24 assessment
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

Per the protocol, the primary clinical efficacy endpoint was "comparison of the vamorolone 6.0 mg/kg/day dose level group versus the placebo group in change from baseline to the Week 24 assessment."

Arm/Group Title	Treatment Group 1	Treatment Group 2
Arm/Group Description	Patients enrolled in Treatment Group 1 (placebo comparator group) will receive placebo for 24 weeks.	Patients enrolled in Treatment Group 2 (experimental group) will receive vamorolone 6.0 mg/kg/day for 24 weeks
Measure Participants	28	27
Mean (Standard Deviation) [Rises/Seconds]	-.007 (0.0628)	0.054 (0.0666)

Adverse Events

Time Frame	Up to 48 weeks
Arm/Group Title	Treatment Group 1		Treatment Group 2		Treatment Group 3		Treatment Group 4		Treatment Group 5		Treatment Group 6
Arm/Group Description	Patients enrolled in Treatment Group 1 (experimental group) will receive vamorolone 2.0 mg/kg/day for 24 weeks followed by vamorolone 2.0mg/kg/day for 20 weeks.		Patients enrolled in Treatment Group 2 (experimental group) will receive vamorolone 6.0 mg/kg/day for 24 weeks followed by vamorolone 6.0mg/kg/day for 20 weeks.		Patients enrolled in Treatment Group 3 (active comparator group) will receive prednisone 0.75 mg/kg/day for 24 weeks followed by vamorolone 2.0mg/kg/day for 20 weeks		Patients enrolled in Treatment Group 4 (active comparator group) will receive prednisone 0.75 mg/kg/day for 24 weeks followed by vamorolone 6.0mg/kg/day for 20 weeks.		Patients enrolled in Treatment Group 5 will receive placebo for 24 weeks followed by vamorolone 2mg/kg/day for 20 weeks.		Patients enrolled in Treatment Group 6 will receive placebo for 24 weeks followed by vamorolone 6mg/kg/day for 20 weeks.
All Cause Mortality
	Treatment Group 1		Treatment Group 2		Treatment Group 3		Treatment Group 4		Treatment Group 5		Treatment Group 6
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/28 (0%)		0/28 (0%)		0/15 (0%)		0/15 (0%)		0/14 (0%)		0/14 (0%)
Serious Adverse Events
	Treatment Group 1		Treatment Group 2		Treatment Group 3		Treatment Group 4		Treatment Group 5		Treatment Group 6
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/28 (3.6%)		2/28 (7.1%)		0/15 (0%)		0/15 (0%)		0/14 (0%)		0/14 (0%)
Infections and infestations
Gastroenteritis viral/viral gasteroenteritis	1/28 (3.6%)		0/28 (0%)		0/15 (0%)		0/15 (0%)		0/14 (0%)		0/14 (0%)
Appendicitis	0/28 (0%)		1/28 (3.6%)		0/15 (0%)		0/15 (0%)		0/14 (0%)		0/14 (0%)
Respiratory, thoracic and mediastinal disorders
Asthma	0/28 (0%)		1/28 (3.6%)		0/15 (0%)		0/15 (0%)		0/14 (0%)		0/14 (0%)
Other (Not Including Serious) Adverse Events
	Treatment Group 1		Treatment Group 2		Treatment Group 3		Treatment Group 4		Treatment Group 5		Treatment Group 6
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	26/28 (92.9%)		26/28 (92.9%)		15/15 (100%)		13/15 (86.7%)		12/14 (85.7%)		14/14 (100%)
Blood and lymphatic system disorders
Leukopenia	0/28 (0%)		0/28 (0%)		0/15 (0%)		1/15 (6.7%)		0/14 (0%)		0/14 (0%)
Ear and labyrinth disorders
Ear pain	0/28 (0%)		1/28 (3.6%)		1/15 (6.7%)		1/15 (6.7%)		0/14 (0%)		0/14 (0%)
Tympanic membrane perforation	0/28 (0%)		0/28 (0%)		0/15 (0%)		1/15 (6.7%)		0/14 (0%)		0/14 (0%)
Endocrine disorders
Cushingoid	4/28 (14.3%)		9/28 (32.1%)		4/15 (26.7%)		4/15 (26.7%)		1/14 (7.1%)		1/14 (7.1%)
Growth hormone deficiency	0/28 (0%)		0/28 (0%)		0/15 (0%)		0/15 (0%)		0/14 (0%)		1/14 (7.1%)
Gastrointestinal disorders
Abdominal Pain	3/28 (10.7%)		3/28 (10.7%)		2/15 (13.3%)		1/15 (6.7%)		2/14 (14.3%)		0/14 (0%)
Abdominal Pain upper	1/28 (3.6%)		3/28 (10.7%)		3/15 (20%)		2/15 (13.3%)		1/14 (7.1%)		1/14 (7.1%)
Constipation	3/28 (10.7%)		3/28 (10.7%)		0/15 (0%)		2/15 (13.3%)		1/14 (7.1%)		1/14 (7.1%)
Diarrhoea	3/28 (10.7%)		5/28 (17.9%)		1/15 (6.7%)		1/15 (6.7%)		0/14 (0%)		1/14 (7.1%)
Vomiting	6/28 (21.4%)		6/28 (21.4%)		1/15 (6.7%)		0/15 (0%)		0/14 (0%)		3/14 (21.4%)
Mouth Ulceration	0/28 (0%)		2/28 (7.1%)		0/15 (0%)		0/15 (0%)		0/14 (0%)		0/14 (0%)
Toothache	1/28 (3.6%)		1/28 (3.6%)		1/15 (6.7%)		0/15 (0%)		0/14 (0%)		0/14 (0%)
Diarrhoea haemorrhagic	0/28 (0%)		0/28 (0%)		0/15 (0%)		0/15 (0%)		1/14 (7.1%)		0/14 (0%)
Flatulance	0/28 (0%)		0/28 (0%)		0/15 (0%)		1/15 (6.7%)		0/14 (0%)		0/14 (0%)
General disorders
Pyrexia	7/28 (25%)		3/28 (10.7%)		3/15 (20%)		1/15 (6.7%)		3/14 (21.4%)		3/14 (21.4%)
Asthenia	0/28 (0%)		0/28 (0%)		0/15 (0%)		1/15 (6.7%)		0/14 (0%)		0/14 (0%)
Fatigue	1/28 (3.6%)		0/28 (0%)		2/15 (13.3%)		2/15 (13.3%)		0/14 (0%)		0/14 (0%)
Impaired healing	0/28 (0%)		0/28 (0%)		0/15 (0%)		1/15 (6.7%)		0/14 (0%)		0/14 (0%)
Thirst	0/28 (0%)		0/28 (0%)		0/15 (0%)		1/15 (6.7%)		0/14 (0%)		0/14 (0%)
Hepatobiliary disorders
Hepatomegaly	0/28 (0%)		0/28 (0%)		0/15 (0%)		0/15 (0%)		1/14 (7.1%)		0/14 (0%)
Infections and infestations
Gasteroenteritis	0/28 (0%)		1/28 (3.6%)		2/15 (13.3%)		0/15 (0%)		1/14 (7.1%)		1/14 (7.1%)
Nasopharyngitis	2/28 (7.1%)		4/28 (14.3%)		3/15 (20%)		2/15 (13.3%)		1/14 (7.1%)		2/14 (14.3%)
Upper respiratory tract infection	10/28 (35.7%)		4/28 (14.3%)		2/15 (13.3%)		3/15 (20%)		3/14 (21.4%)		2/14 (14.3%)
Rhinitis	2/28 (7.1%)		4/28 (14.3%)		0/15 (0%)		0/15 (0%)		0/14 (0%)		2/14 (14.3%)
Enterobiasis	1/28 (3.6%)		2/28 (7.1%)		0/15 (0%)		0/15 (0%)		0/14 (0%)		0/14 (0%)
Conjunctivitis	0/28 (0%)		1/28 (3.6%)		0/15 (0%)		0/15 (0%)		0/14 (0%)		1/14 (7.1%)
Ear Infection	1/28 (3.6%)		1/28 (3.6%)		0/15 (0%)		1/15 (6.7%)		1/14 (7.1%)		1/14 (7.1%)
Gastroenteritis	0/28 (0%)		1/28 (3.6%)		2/15 (13.3%)		0/15 (0%)		1/14 (7.1%)		1/14 (7.1%)
Tonsilitis	1/28 (3.6%)		1/28 (3.6%)		0/15 (0%)		0/15 (0%)		2/14 (14.3%)		0/14 (0%)
Viral Infection	0/28 (0%)		1/28 (3.6%)		0/15 (0%)		0/15 (0%)		1/14 (7.1%)		0/14 (0%)
COVID-19	0/28 (0%)		0/28 (0%)		0/15 (0%)		1/15 (6.7%)		0/14 (0%)		1/14 (7.1%)
Cystitis	0/28 (0%)		0/28 (0%)		1/15 (6.7%)		0/15 (0%)		0/14 (0%)		0/14 (0%)
Fungal Infection	0/28 (0%)		0/28 (0%)		1/15 (6.7%)		0/15 (0%)		0/14 (0%)		0/14 (0%)
Gastroenteritis viral/viral gasteroenteritis	3/28 (10.7%)		0/28 (0%)		1/15 (6.7%)		0/15 (0%)		0/14 (0%)		0/14 (0%)
Hand-foot-and-mouth disease	0/28 (0%)		0/28 (0%)		0/15 (0%)		0/15 (0%)		0/14 (0%)		1/14 (7.1%)
Impetigo	2/28 (7.1%)		0/28 (0%)		0/15 (0%)		0/15 (0%)		0/14 (0%)		0/14 (0%)
Influenza	1/28 (3.6%)		0/28 (0%)		1/15 (6.7%)		0/15 (0%)		2/14 (14.3%)		0/14 (0%)
Moluscum contagiosum	0/28 (0%)		0/28 (0%)		0/15 (0%)		0/15 (0%)		0/14 (0%)		1/14 (7.1%)
Otitis media bacterial	0/28 (0%)		0/28 (0%)		0/15 (0%)		0/15 (0%)		1/14 (7.1%)		0/14 (0%)
Pharyngitis streptococcal	1/28 (3.6%)		0/28 (0%)		1/15 (6.7%)		0/15 (0%)		0/14 (0%)		1/14 (7.1%)
Pneumonia	1/28 (3.6%)		0/28 (0%)		0/15 (0%)		0/15 (0%)		1/14 (7.1%)		0/14 (0%)
Respiratory track infection viral	0/28 (0%)		0/28 (0%)		0/15 (0%)		1/15 (6.7%)		0/14 (0%)		0/14 (0%)
Steptococcal infection	0/28 (0%)		0/28 (0%)		1/15 (6.7%)		0/15 (0%)		0/14 (0%)		0/14 (0%)
Tooth infection	0/28 (0%)		0/28 (0%)		1/15 (6.7%)		0/15 (0%)		0/14 (0%)		0/14 (0%)
Viral upper respiratory tract infection	0/28 (0%)		0/28 (0%)		0/15 (0%)		1/15 (6.7%)		0/14 (0%)		0/14 (0%)
Injury, poisoning and procedural complications
Arthropod bite	1/28 (3.6%)		2/28 (7.1%)		0/15 (0%)		0/15 (0%)		1/14 (7.1%)		1/14 (7.1%)
Contusion	2/28 (7.1%)		1/28 (3.6%)		1/15 (6.7%)		0/15 (0%)		0/14 (0%)		0/14 (0%)
Fall	2/28 (7.1%)		4/28 (14.3%)		2/15 (13.3%)		3/15 (20%)		0/14 (0%)		1/14 (7.1%)
Ligament strain	1/28 (3.6%)		1/28 (3.6%)		0/15 (0%)		0/15 (0%)		1/14 (7.1%)		0/14 (0%)
Back injury	0/28 (0%)		0/28 (0%)		0/15 (0%)		1/15 (6.7%)		0/14 (0%)		0/14 (0%)
Muscle strain	1/28 (3.6%)		0/28 (0%)		0/15 (0%)		1/15 (6.7%)		0/14 (0%)		0/14 (0%)
Vaccination complication	0/28 (0%)		0/28 (0%)		1/15 (6.7%)		0/15 (0%)		0/14 (0%)		0/14 (0%)
Investigations
Blood uric acid increased	1/28 (3.6%)		0/28 (0%)		0/15 (0%)		2/15 (13.3%)		0/14 (0%)		1/14 (7.1%)
Protein Urine Present	1/28 (3.6%)		0/28 (0%)		1/15 (6.7%)		3/15 (20%)		0/14 (0%)		0/14 (0%)
Weight increased	1/28 (3.6%)		3/28 (10.7%)		1/15 (6.7%)		1/15 (6.7%)		1/14 (7.1%)		1/14 (7.1%)
Cortisol decreased	1/28 (3.6%)		1/28 (3.6%)		0/15 (0%)		0/15 (0%)		0/14 (0%)		1/14 (7.1%)
Bacterial test postive	0/28 (0%)		0/28 (0%)		0/15 (0%)		1/15 (6.7%)		0/14 (0%)		0/14 (0%)
Blood pressure increased	1/28 (3.6%)		0/28 (0%)		1/15 (6.7%)		0/15 (0%)		1/14 (7.1%)		0/14 (0%)
Blood triglycerides increased	0/28 (0%)		0/28 (0%)		0/15 (0%)		0/15 (0%)		1/14 (7.1%)		0/14 (0%)
Electrocardiogram abnormal	0/28 (0%)		0/28 (0%)		0/15 (0%)		1/15 (6.7%)		0/14 (0%)		0/14 (0%)
Glycosylated haemoglobin increased	0/28 (0%)		0/28 (0%)		0/15 (0%)		1/15 (6.7%)		0/14 (0%)		0/14 (0%)
Lipase decreased	0/28 (0%)		0/28 (0%)		0/15 (0%)		1/15 (6.7%)		0/14 (0%)		0/14 (0%)
Urine analysis abnormal	0/28 (0%)		0/28 (0%)		1/15 (6.7%)		0/15 (0%)		0/14 (0%)		0/14 (0%)
Weight decreased	0/28 (0%)		0/28 (0%)		0/15 (0%)		0/15 (0%)		0/14 (0%)		1/14 (7.1%)
Metabolism and nutrition disorders
Increased appetite	1/28 (3.6%)		2/28 (7.1%)		0/15 (0%)		1/15 (6.7%)		1/14 (7.1%)		0/14 (0%)
Vitamin D Deficiency	2/28 (7.1%)		3/28 (10.7%)		1/15 (6.7%)		2/15 (13.3%)		0/14 (0%)		0/14 (0%)
Decreased appetite	0/28 (0%)		0/28 (0%)		1/15 (6.7%)		1/15 (6.7%)		0/14 (0%)		0/14 (0%)
Hypertriglyceridaemia	0/28 (0%)		0/28 (0%)		0/15 (0%)		1/15 (6.7%)		0/14 (0%)		0/14 (0%)
Overweight	0/28 (0%)		0/28 (0%)		0/15 (0%)		1/15 (6.7%)		0/14 (0%)		0/14 (0%)
Polydipsia	0/28 (0%)		0/28 (0%)		0/15 (0%)		1/15 (6.7%)		0/14 (0%)		0/14 (0%)
Musculoskeletal and connective tissue disorders
Pain in extremity	2/28 (7.1%)		3/28 (10.7%)		4/15 (26.7%)		4/15 (26.7%)		2/14 (14.3%)		0/14 (0%)
Back pain	1/28 (3.6%)		2/28 (7.1%)		0/15 (0%)		1/15 (6.7%)		0/14 (0%)		1/14 (7.1%)
Athralgia	1/28 (3.6%)		1/28 (3.6%)		1/15 (6.7%)		0/15 (0%)		0/14 (0%)		0/14 (0%)
Muscle spasms	0/28 (0%)		1/28 (3.6%)		1/15 (6.7%)		0/15 (0%)		0/14 (0%)		1/14 (7.1%)
Myalgia	0/28 (0%)		1/28 (3.6%)		0/15 (0%)		0/15 (0%)		0/14 (0%)		1/14 (7.1%)
Costrochondritis	0/28 (0%)		0/28 (0%)		0/15 (0%)		0/15 (0%)		0/14 (0%)		1/14 (7.1%)
Joint contracture	0/28 (0%)		0/28 (0%)		0/15 (0%)		0/15 (0%)		0/14 (0%)		1/14 (7.1%)
Joint swelling	0/28 (0%)		0/28 (0%)		0/15 (0%)		0/15 (0%)		0/14 (0%)		1/14 (7.1%)
Muscle atrophy	1/28 (3.6%)		0/28 (0%)		0/15 (0%)		0/15 (0%)		1/14 (7.1%)		0/14 (0%)
Muscular weakness	0/28 (0%)		0/28 (0%)		0/15 (0%)		0/15 (0%)		1/14 (7.1%)		0/14 (0%)
Musculoskeletal pain	0/28 (0%)		0/28 (0%)		0/15 (0%)		0/15 (0%)		1/14 (7.1%)		0/14 (0%)
Musculoskeletal stiffness	0/28 (0%)		0/28 (0%)		0/15 (0%)		1/15 (6.7%)		0/14 (0%)		0/14 (0%)
Vertebral wedging	0/28 (0%)		0/28 (0%)		0/15 (0%)		1/15 (6.7%)		0/14 (0%)		0/14 (0%)
Agitation	0/28 (0%)		1/28 (3.6%)		1/15 (6.7%)		1/15 (6.7%)		0/14 (0%)		0/14 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Skin papilloma	0/28 (0%)		0/28 (0%)		0/15 (0%)		0/15 (0%)		0/14 (0%)		1/14 (7.1%)
Nervous system disorders
Headache	3/28 (10.7%)		2/28 (7.1%)		1/15 (6.7%)		1/15 (6.7%)		0/14 (0%)		3/14 (21.4%)
Psychomotor hyperactivity	2/28 (7.1%)		0/28 (0%)		1/15 (6.7%)		2/15 (13.3%)		0/14 (0%)		0/14 (0%)
Dizziness	0/28 (0%)		0/28 (0%)		0/15 (0%)		0/15 (0%)		0/14 (0%)		1/14 (7.1%)
Poor quality sleep	1/28 (3.6%)		0/28 (0%)		0/15 (0%)		1/15 (6.7%)		0/14 (0%)		0/14 (0%)
Seizure	0/28 (0%)		0/28 (0%)		0/15 (0%)		0/15 (0%)		1/14 (7.1%)		0/14 (0%)
Syncope	0/28 (0%)		0/28 (0%)		0/15 (0%)		1/15 (6.7%)		0/14 (0%)		0/14 (0%)
Psychiatric disorders
Abnormal behaviour	2/28 (7.1%)		1/28 (3.6%)		2/15 (13.3%)		0/15 (0%)		1/14 (7.1%)		1/14 (7.1%)
Aggression	2/28 (7.1%)		1/28 (3.6%)		0/15 (0%)		2/15 (13.3%)		1/14 (7.1%)		0/14 (0%)
Irritability	0/28 (0%)		3/28 (10.7%)		1/15 (6.7%)		0/15 (0%)		0/14 (0%)		1/14 (7.1%)
Sleep disorder	0/28 (0%)		1/28 (3.6%)		1/15 (6.7%)		0/15 (0%)		1/14 (7.1%)		0/14 (0%)
Anger	0/28 (0%)		0/28 (0%)		1/15 (6.7%)		1/15 (6.7%)		0/14 (0%)		0/14 (0%)
Dysphemia	0/28 (0%)		0/28 (0%)		1/15 (6.7%)		0/15 (0%)		0/14 (0%)		0/14 (0%)
Emotional disorder	0/28 (0%)		0/28 (0%)		0/15 (0%)		1/15 (6.7%)		0/14 (0%)		0/14 (0%)
Enuresis	0/28 (0%)		0/28 (0%)		0/15 (0%)		0/15 (0%)		1/14 (7.1%)		0/14 (0%)
Initial insomnia	0/28 (0%)		0/28 (0%)		0/15 (0%)		1/15 (6.7%)		0/14 (0%)		0/14 (0%)
Insomnia	0/28 (0%)		0/28 (0%)		0/15 (0%)		0/15 (0%)		0/14 (0%)		1/14 (7.1%)
Mood swings	0/28 (0%)		0/28 (0%)		0/15 (0%)		1/15 (6.7%)		1/14 (7.1%)		0/14 (0%)
Oppositional defiant disorder	0/28 (0%)		0/28 (0%)		0/15 (0%)		1/15 (6.7%)		0/14 (0%)		0/14 (0%)
Personality change	0/28 (0%)		0/28 (0%)		1/15 (6.7%)		0/15 (0%)		0/14 (0%)		0/14 (0%)
Trichotillomania	0/28 (0%)		0/28 (0%)		0/15 (0%)		1/15 (6.7%)		0/14 (0%)		0/14 (0%)
Epistaxis	0/28 (0%)		1/28 (3.6%)		0/15 (0%)		1/15 (6.7%)		1/14 (7.1%)		0/14 (0%)
Night sweats	0/28 (0%)		0/28 (0%)		0/15 (0%)		1/15 (6.7%)		0/14 (0%)		0/14 (0%)
Renal and urinary disorders
Chromaturia	0/28 (0%)		1/28 (3.6%)		1/15 (6.7%)		1/15 (6.7%)		0/14 (0%)		0/14 (0%)
Proteinuria	1/28 (3.6%)		0/28 (0%)		0/15 (0%)		0/15 (0%)		0/14 (0%)		1/14 (7.1%)
Respiratory, thoracic and mediastinal disorders
Cough	5/28 (17.9%)		3/28 (10.7%)		2/15 (13.3%)		4/15 (26.7%)		0/14 (0%)		2/14 (14.3%)
Nasal congestion	0/28 (0%)		2/28 (7.1%)		1/15 (6.7%)		2/15 (13.3%)		0/14 (0%)		0/14 (0%)
Rhinorrhoea	1/28 (3.6%)		1/28 (3.6%)		0/15 (0%)		1/15 (6.7%)		0/14 (0%)		1/14 (7.1%)
Oropharyngeal pain	1/28 (3.6%)		0/28 (0%)		1/15 (6.7%)		1/15 (6.7%)		0/14 (0%)		1/14 (7.1%)
Skin and subcutaneous tissue disorders
Hypertrichosis	1/28 (3.6%)		3/28 (10.7%)		1/15 (6.7%)		1/15 (6.7%)		0/14 (0%)		1/14 (7.1%)
Rash	2/28 (7.1%)		2/28 (7.1%)		2/15 (13.3%)		2/15 (13.3%)		1/14 (7.1%)		2/14 (14.3%)
Eczema	0/28 (0%)		1/28 (3.6%)		0/15 (0%)		0/15 (0%)		0/14 (0%)		1/14 (7.1%)
Perioral dermatitis	0/28 (0%)		1/28 (3.6%)		0/15 (0%)		1/15 (6.7%)		0/14 (0%)		0/14 (0%)
Pruritis	0/28 (0%)		1/28 (3.6%)		1/15 (6.7%)		0/15 (0%)		0/14 (0%)		0/14 (0%)
Dry skin	1/28 (3.6%)		0/28 (0%)		0/15 (0%)		1/15 (6.7%)		0/14 (0%)		0/14 (0%)
Erythema	1/28 (3.6%)		0/28 (0%)		0/15 (0%)		0/15 (0%)		1/14 (7.1%)		0/14 (0%)
Rash macropapular	0/28 (0%)		0/28 (0%)		1/15 (6.7%)		0/15 (0%)		0/14 (0%)		0/14 (0%)
Urticaria	0/28 (0%)		0/28 (0%)		0/15 (0%)		0/15 (0%)		0/14 (0%)		1/14 (7.1%)
Viral rash	0/28 (0%)		0/28 (0%)		0/15 (0%)		1/15 (6.7%)		0/14 (0%)		0/14 (0%)
Vascular disorders
Hot flush	0/28 (0%)		0/28 (0%)		0/15 (0%)		1/15 (6.7%)		0/14 (0%)		0/14 (0%)
Peripheral coldness	0/28 (0%)		0/28 (0%)		0/15 (0%)		1/15 (6.7%)		0/14 (0%)		0/14 (0%)

Limitations/Caveats

[Not Specified]

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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.