Ph 3 Efficacy and Safety of B-VEC for the Treatment of DEB (GEM-3)

• ClinicalTrials.gov Identifier: NCT04491604
• Recruitment Status: Completed
• First Posted: July 29, 2020
• Results First Posted: February 17, 2023
• Last Update Posted: February 17, 2023
• Sponsor: Krystal Biotech, Inc.
• Information provided by (Responsible Party): Krystal Biotech, Inc.

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Conditions: Dystrophic Epidermolysis Bullosa; Recessive Dystrophic Epidermolysis Bullosa; Dominant Dystrophic Epidermolysis Bullosa
• Interventions: Biological: Topical Beremagene Geperpavec; Other: Placebo
• Enrollment: 31

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	All Participants ("Topical Beremagene Geperpavec (B-VEC)", and "Placebo")
Arm/Group Description	Each subject provided one pair of primary target wounds, with one wound from each pair randomized to be treated with B-VEC and the other wound with placebo.
Period Title: Overall Study
	Number of participants	Number of units (Wounds)
Started	31 [1]	62
B-VEC	31	31
Placebo	31	31
Completed	28	56
Not Completed	3	6
Reason Not Completed
Withdrawal by Subject	3
[1] Each subject provided one pair of primary target wounds, with one wound from each pair randomized to be treated with B-VEC and the other wound with placebo. The total primary wounds selected were 62 (=2x31), in which 31 each received B-VEC and Placebo, respectively. Additional wounds ("Secondary Wounds") were selected using the remaining weekly B-VEC dose. The number of Secondary Wounds treated depended on wound areas. The Secondary Wounds related data were not analyzed per protocol.

Baseline Characteristics

Arm/Group Title		All Participants ("Topical Beremagene Geperpavec (B-VEC)", and "Placebo")
Arm/Group Description		Each subject provided one pair of primary target wounds, with one wound from each pair randomized to be treated with B-VEC and the other wound with placebo.
Overall Number of Baseline Participants		31
Baseline Analysis Population Description		Safety Population
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	31 participants
		17.2 (10.70)
Age, Customized; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	31 participants
	<= 12 years	10 32.3%
	> 12 and <= 18 years	9 29.0%
	> 18 years	12 38.7%
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	31 participants
	Female	11 35.5%
	Male	20 64.5%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	31 participants
	Hispanic or Latino	16 51.6%
	Not Hispanic or Latino	15 48.4%
	Unknown or Not Reported	0 0.0%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	31 participants
	American Indian or Alaska Native	5 16.1%
	Asian	6 19.4%
	Native Hawaiian or Other Pacific Islander	0 0.0%
	Black or African American	0 0.0%
	White	20 64.5%
	More than one race	0 0.0%
	Unknown or Not Reported	0 0.0%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
United States	Number Analyzed	31 participants
		31
Primary Wound Area(cm^2) B-VEC; Mean (Standard Deviation); Unit of measure: Cm^2
	Number Analyzed	31 participants
		14.354 (12.6930)
Primary Wound Area(cm^2) Placebo; Mean (Standard Deviation); Unit of measure: Cm^2
	Number Analyzed	31 participants
		15.565 (12.1315)

Outcome Measures

1. Primary Outcome

Title	Primary Wound With Complete Wound Healing (100% Wound Closure) on Weeks 22 and 24 or Weeks 24 and 26
Description	The primary wound was defined as a responder wound that met either of the following conditions: Complete wound healing on Week 22 and Week 24, or; Complete wound healing on Week 24 and Week 26. For subjects with missing primary wound healing data, a multiple imputation approach (10 repliates) was used. The total numbers of primary wounds with complete healing for B-VEC and Placebo presented below were the average of those from the multiple imputation replicates, and therefore, they would not be whole numbers (integers).
Time Frame	26 weeks post-baseline

Outcome Measure Data

Analysis Population Description

The intent-to-treat (ITT) population included subjects whose primary wounds were randomized regardless of whether they received randomized treatment or not.

Arm/Group Title	B-VEC	Placebo
Arm/Group Description:	Topical gel of non-integrating, replication-incompetent HSV-1 expressing the human collagen VII protein	Matching masked inactive topical gel
Overall Number of Participants Analyzed	31	31
Overall Number of Units Analyzed; Type of Units Analyzed: Wounds	31	31
Measure Type: Number; Unit of Measure: number of wounds with complete healing
	20.9	6.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	B-VEC, Placebo
	Comments	The null hypothesis of interest was the absence of a treatment effect on wound healing and the alternative hypothesis is the presence of a treatment effect on wound healing. The Hypothesis was tested by exact McNemar's test on the paired primary wound healing data. For subjects with missing primary wound healing data, a multiple imputation approach was used.
	Type of Statistical Test	Equivalence
	Comments	The Hypothesis was tested by exact McNemar's test on the paired primary wound healing data.
Statistical Test of Hypothesis	P-Value	0.00192
	Comments	[Not Specified]
	Method	McNemar
	Comments	The Hypothesis was tested by exact McNemar's test on the paired primary wound healing data. A multiple imputation approach was used for missing data.
Method of Estimation	Estimation Parameter	responder rate difference
	Estimated Value	45.8
	Confidence Interval	(2-Sided) 95%; 23.6 to 68.0
	Estimation Comments	The difference is the treatment/discordance difference in percentage of responders (primary wounds with complete healing), which is the same as the difference in the percentage of treatment responders and the percentage of placebo responders.

2. Secondary Outcome

Title	Primary Wound With Complete Wound Healing (100% Wound Closure) on Weeks 8 and 10 or Weeks 10 and 12
Description	The primary wound was defined as a responder wound that met either of the following conditions: Complete wound healing on Week 8 and Week 10, or; Complete wound healing on Week 10 and Week 12. For subjects with missing primary wound healing data, a multiple imputation approach (10 repliates) was used. The total numbers of primary wounds with complete healing for B-VEC and Placebo presented below were the average of those from the multiple imputation replicates, and therefore, they would not be whole numbers (integers).
Time Frame	12 weeks post-baseline

Outcome Measure Data

Analysis Population Description

The intent-to-treat (ITT) population included subjects whose primary wounds were randomized regardless of whether they received randomized treatment or not.

Arm/Group Title	B-VEC	Placebo
Arm/Group Description:	Topical gel of non-integrating, replication-incompetent HSV-1 expressing the human collagen VII protein	Matching masked inactive topical gel
Overall Number of Participants Analyzed	31	31
Overall Number of Units Analyzed; Type of Units Analyzed: Wounds	31	31
Measure Type: Number; Unit of Measure: number of wounds with complete healing
	21.9	6.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	B-VEC, Placebo
	Comments	The null hypothesis of interest was the absence of a treatment effect on wound healing and the alternative hypothesis is the presence of a treatment effect on wound healing. The Hypothesis was tested by exact McNemar's test on the paired primary wound healing data. For subjects with missing primary wound healing data, a multiple imputation approach was used.
	Type of Statistical Test	Equivalence
	Comments	The Hypothesis was tested by exact McNemar's test on the paired primary wound healing data.
Statistical Test of Hypothesis	P-Value	0.00047
	Comments	There is no multiplicity adjustment needed since the hypothesis testing are hierarchical.
	Method	McNemar
	Comments	The Hypothesis was tested by exact McNemar's test on the paired primary wound healing data. A multiple imputation approach was used for missing data.
Method of Estimation	Estimation Parameter	responder rate difference
	Estimated Value	51.0
	Confidence Interval	(2-Sided) 95%; 29.3 to 72.6
	Estimation Comments	The difference is the treatment/discordance difference in percentage of responders (complete wound healing), which is the same as the difference in the percentage of treatment responders and the percentage of placebo responders.

3. Secondary Outcome

Title	Primary Wound Pain Severity (Visual Analog Scale (VAS)) Change for Ages 6 and Above Subjects at Weeks 22, 24, and 26.
Description	Changes from baseline at Weeks 22, 24, and 26 in primary wound pain severity (visual analog scale (VAS)) for ages 6 and above subjects. The Visual Analog Scale scores from 0 (no pain) to 10 (the worst possible pain). Negative values in changes from baseline mean improvement in pain severity.
Time Frame	26 weeks post-baseline

Outcome Measure Data

Analysis Population Description

The intent-to-treat (ITT) population included subjects whose primary wounds were randomized regardless of whether they received randomized treatment or not. For pain severity, only subjects ages 6 and above were evaluated (n=27). The analyses were based on observed data where missing data were not imputed, therefore the numbers of available data for analyses could be less than the total.

Arm/Group Title		B-VEC	Placebo
Arm/Group Description:		Topical gel of non-integrating, replication-incompetent HSV-1 expressing the human collagen VII protein	Matching masked inactive topical gel
Overall Number of Participants Analyzed		27	27
Mean (Standard Deviation); Unit of Measure: score on a scale of 0 to 10
Week 22	Number Analyzed	24 participants	24 participants
		-0.88 (2.346)	-0.71 (2.476)
Week 24	Number Analyzed	25 participants	25 participants
		-0.64 (2.325)	-0.08 (2.548)
Week 26	Number Analyzed	24 participants	24 participants
		-0.63 (2.123)	-0.38 (2.871)

Adverse Events

Time Frame	6 months
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	All Participants ("Topical Beremagene Geperpavec (B-VEC)", and "Placebo")
Arm/Group Description	Each subject provided one pair of primary target wounds, with one wound from each pair randomized to be treated with B-VEC and the other wound with placebo. Due to the 'split-person'/intrasubject design, each subject received both B-VEC and Placebo. Therefore, the safety assessments were reported at subject level, but not per intervention.
All-Cause Mortality
	All Participants ("Topical Beremagene Geperpavec (B-VEC)", and "Placebo")
	Affected / at Risk (%)
Total	0/31 (0.00%)
Serious Adverse Events
	All Participants ("Topical Beremagene Geperpavec (B-VEC)", and "Placebo")
	Affected / at Risk (%)	# Events
Total	3/31 (9.68%)
Blood and lymphatic system disorders
Anaemia † [1]	1/31 (3.23%)	2
Gastrointestinal disorders
Diarrhoea † [2]	1/31 (3.23%)	1
Infections and infestations
Cellulitis † [3]	1/31 (3.23%)	1
Investigations
Blood culture positive † [4]	1/31 (3.23%)	1
† Indicates events were collected by systematic assessment; [1] severe anemia; [2] Diarrhoea; [3] cellulitis of the right leg; [4] Blood culture positive
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	All Participants ("Topical Beremagene Geperpavec (B-VEC)", and "Placebo")
	Affected / at Risk (%)	# Events
Total	17/31 (54.84%)
General disorders
Chills †	3/31 (9.68%)	3
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Squamous cell carcinoma †	3/31 (9.68%)	4
Respiratory, thoracic and mediastinal disorders
Cough †	2/31 (6.45%)	2
Rhinorrhoea †	2/31 (6.45%)	2
Skin and subcutaneous tissue disorders
Pruritus †	3/31 (9.68%)	4
Erythema †	2/31 (6.45%)	2
Rash †	2/31 (6.45%)	2
† Indicates events were collected by systematic assessment

Limitations and 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.

Results Point of Contact

• Name/Title: Dr. Hubert Chen, MD, Senior Vice President of Clinical Development
• Organization: Krystal Biotech
• Phone: (412) 586-5830
• EMail: inquiries@krystalbio.com

• Responsible Party: Krystal Biotech, Inc.
• ClinicalTrials.gov Identifier: NCT04491604
• Other Study ID Numbers: B-VEC-03
• First Submitted: July 22, 2020
• First Posted: July 29, 2020
• Results First Submitted: December 8, 2022
• Results First Posted: February 17, 2023
• Last Update Posted: February 17, 2023