GS-5734 to Assess the Antiviral Activity, Longer-Term Clearance of Ebola Virus, and Safety in Male Ebola Survivors With Evidence of Ebola Virus Persistence in Semen

• ClinicalTrials.gov Identifier: NCT02818582
• Recruitment Status: Completed
• First Posted: June 29, 2016
• Last Update Posted: October 9, 2019
• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )

Tracking Information

• First Submitted Date: June 28, 2016
• First Posted Date: June 29, 2016
• Last Update Posted Date: October 9, 2019
• Actual Study Start Date: July 1, 2016
• Actual Primary Completion Date: October 7, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 27, 2019)

• Treatment phase: To compare the antiviral activity over 28 days following the administration of 5 days of IV GS-5734 versus placebo in male Ebola Virus Disease survivors with evidence of Ebola virus RNA in their semen. [ Time Frame: Day 4, 8, 11, 16, 24, and 28 ]
  Treatment phase: Assay Negativity Rate (ANR) over days 4, 8, 11, 16, 24, and 28.
• Follow-up phase: To compare the effect of 5 days of IV GS- 5734 versus placebo on the detection of Ebola virus RNA in semen of male survivors of Ebola Virus Disease over 24 weeks [ Time Frame: Week 8, 12, 16, 20, 24 ]
  Follow-up phase: Assay Negativity Rate (ANR) over weeks 8, 12, 16, 20, and 24.

Original Primary Outcome Measures (submitted: June 28, 2016)

• To compare the antiviral activity over 28 days following the administration of 5 days of IV GS-5734 versus placebo in male Ebola Virus Disease survivors with evidence of Ebola virus in their semen. [ Time Frame: 28 days ]
• To compare the effect of 5 days of IV GS-5734 versus placebo on the detection of Ebola RNA in semen of male survivors of Ebola Virus Disease over 24 weeks. [ Time Frame: 24 weeks ]

Current Secondary Outcome Measures (submitted: July 27, 2019)

• To evaluate the safety and tolerability of GS-5734 in male Ebola survivors with evidence of Ebola virus RNA in their semen [ Time Frame: days 1, 2, 3, 4, 5, 8, 11, 16, 24, and 28. ]
  Proportion of Grade 1, Grade 2, Grade 3, or Grade 4 aspartate transaminase (AST) and alanine transaminase (ALT) levels at days 1, 2, 3, 4, 5, 8, 11, 16, 24, and 28
• To evaluate 24-week safety outcomes following IV GS- 5734 treatment in male Ebola survivors [ Time Frame: weeks 8, 12, 16, 20, and 24 ]
  Sustained Negativity Rate at weeks 8, 12, 16, 20, and 24.

Original Secondary Outcome Measures (submitted: June 28, 2016)

• To evaluate the safety and tolerability of GS-5734 in male Ebola survivors with evidence of Ebola virus in their semen. [ Time Frame: 28 weeks ]
• To evaluate the pharmacokinetics of GS-5734 (and metabolites as appropriate) in blood and PBMCs. [ Time Frame: Day 5 ]
• To compare the antiviral activity over 28 days following the administration of 5 days of IV GS-5734 versus placebo in subjects with a CT value of either the GP or NP targets of less than or equal to 39 in at least one semen sample during the 42 ... [ Time Frame: 28 weeks ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: GS-5734 to Assess the Antiviral Activity, Longer-Term Clearance of Ebola Virus, and Safety in Male Ebola Survivors With Evidence of Ebola Virus Persistence in Semen
• Official Title: PREVAIL IV: Double-Blind, Randomized, Two-Phase, Placebo-Controlled, Phase II Trial of GS-5734 to Assess the Antiviral Activity, Longer-Term Clearance of Ebola Virus, and Safety in Male Ebola Survivors With Evidence of Ebola Virus Persistence in Semen

Brief Summary

Background:

Some people have Ebola virus in their body for months after they recover from Ebola virus disease. Some may have health problems from the virus while others are fine. These people may be able to pass the virus to others. There are currently no drugs for people who have survived Ebola virus disease but still have the virus in their body. A new drug, GS-5734, might help get rid of Ebola virus in semen.

Objective:

To test if GS-5734 helps get rid of Ebola virus in semen and is safe for humans.

Eligibility:

Men who participated in the Ebola survivor study (PREVAIL III) and have evidence of the Ebola virus in their semen

Design:

Participants will be screened with:

Questions

Physical exam

Eye exam

Blood tests

2 semen samples if they have not had it tested recently

Participants must live near the study site in Liberia for 6 months.

Participants will be put into 1 of 2 study groups. They will have an infusion of either GS-5734 or a placebo every day for 5 days. A plastic tube is put into an arm vein. The infusion lasts 1 hour.

Participants will be observed for 1 hour after. They will provide a semen sample on infusion day 4.

After the infusions, participants will have 5 visits in the first month, then 1 per month for 5 more months. These include giving a blood and semen sample.

Blood tests are performed before and after each infusion and the last visit (5 month visit) will also include an eye exam.

When the study is over, if the study drug works and is safe, participants who got the placebo can get the study drug.

Detailed Description

With the unprecedented size of the recent 2014-2016 West African Ebola outbreak, the scientific community is learning a great deal about the psychological and physical consequences of Ebola, Ebola viral persistence in survivors, risk of Ebola disease relapse in survivors, and the potential for survivors to transmit the virus to others. Data from PREVAIL III has demonstrated that persistence of Ebola virus in the semen of male survivors is common. In addition to Ebola virus persistence, Ebola relapse causing clinical disease has been well documented.

There are no licensed therapies for the treatment of Ebola virus disease nor for the clearance of persistent Ebola virus in survivors. A safe, effective therapy that can reduce and/or eliminate persistent Ebola virus from semen would reduce the risk of transmission and enable male survivors to resume normal sexual relations without fear of harming loved ones. The mechanism underlying Post-Ebola Syndrome is as yet unknown, but improvement in Post-Ebola signs and symptoms resulting from GS-5734 treatment would be an added benefit.

This study is a double-blind, randomized, two-phase (treatment and longer-term follow-up), two- arm trial of GS-5734 versus placebo among male Ebola survivors with persistent Ebola virus RNA in their semen. Participants are randomized 1:1 to receive either 100 mg of GS-5734 or placebo once daily by intravenous catheter for 5 days. Informed by transaminase elevations in prior Phase I studies in normal healthy subjects, a risk-mitigation strategy includes a built-in dose de-escalation. Participants will be stratified by country and on the basis of one versus two positive semen samples for Ebola virus RNA using the Cepheid GeneXpert platform assessed within 42 days prior to study enrollment. The early DSMB review in August 2016 concluded there was no need for a cohort dose reduction. The protocol expanded to Guinea in October 2017, where the outbreak ended later. Currently there is an outbreak in the Democratic Republic of the Congo where the study team may evaluate conducting this study following the completion of the outbreak.

Antiviral activity, as well as safety and tolerability, will be assessed during the treatment phase. Longer-term clearance of Ebola virus will be assessed during the 5-month follow-up phase. Primary analyses for the assessment of antiviral activity in the treatment phase will focus on the assay negativity rate (ANR; percentage of genital samples that are negative for Ebola) over the first 28 days of the study, as well as clinical and laboratory adverse events. A sample is considered negative by PCR if the test result is undetectable. Primary analysis for the follow-up phase will focus on the ANR collected monthly from months 2 to 6.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Ebola

Intervention

• Drug: GS-5734
  Daily GS-5734 or placebo delivered intravenously (IV) for 5 days
• Other: Placebo Comparator
  Placebo delivered intravenously (IV) for 5 days.

Study Arms

• Active Comparator: 1
  Active
  Intervention: Drug: GS-5734
• Placebo Comparator: 2
  Placebo
  Intervention: Other: Placebo Comparator

Publications *

• de Vries DH, Rwemisisi JT, Musinguzi LK, Benoni TE, Muhangi D, de Groot M, Kaawa-Mafigiri D, Pool R. The first mile: community experience of outbreak control during an Ebola outbreak in Luwero District, Uganda. BMC Public Health. 2016 Feb 16;16:161. doi: 10.1186/s12889-016-2852-0.
• Bwaka MA, Bonnet MJ, Calain P, Colebunders R, De Roo A, Guimard Y, Katwiki KR, Kibadi K, Kipasa MA, Kuvula KJ, Mapanda BB, Massamba M, Mupapa KD, Muyembe-Tamfum JJ, Ndaberey E, Peters CJ, Rollin PE, Van den Enden E, Van den Enden E. Ebola hemorrhagic fever in Kikwit, Democratic Republic of the Congo: clinical observations in 103 patients. J Infect Dis. 1999 Feb;179 Suppl 1:S1-7.
• Feldmann H, Geisbert TW. Ebola haemorrhagic fever. Lancet. 2011 Mar 5;377(9768):849-62. doi: 10.1016/S0140-6736(10)60667-8. Review.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: October 8, 2019): 38
• Original Estimated Enrollment (submitted: June 28, 2016): 120
• Actual Study Completion Date: October 7, 2019
• Actual Primary Completion Date: October 7, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

• INCLUSION CRITERIA:

Individuals must meet all of the following criteria to be eligible for study participation:

• Men more than or equal to 18 years of age.
• One of two semen samples with Ebola virus RNA detection (defined as a positive PCR for NP or GP using the GeneXpert assay within 42 days prior to randomization).
• Willingness to be available for study evaluations for 6 months.
• Willingness to allow storage of biological samples.
• Willingness to be followed by a Participant Tracker.
• Willingness to refrain from alcohol consumption for study days -7 to 14.
• Willingness to comply with MOH & CDC guidance on using a condom for sexual activity and at least through week 24 of the study.

EXCLUSION CRITERIA:

Individuals meeting any of the following criteria will be excluded from study participation:

• Estimated glomerular filtration rate less than 60 mL/min/1.73m^2
• History of significant renal disease
• History of significant liver disease
• Evidence of liver disease on physical exam such as ascites
• AST or ALT, greater than the upper limit of normal, a prothrombin time 1.1 times greater than the upper limits of normal, normal, or a total bilirubin > 1.5 times the upper limits of normal(per DAIDS toxicity tables version 2.0 Nov. 2014).
• Presence of Grade 2 or higher abnormalities for: low hemoglobin, low white blood count (WBC), low platelets, or low or high potassium (per DAIDS toxicity tables version 2.0 Nov. 2014).
• Presence of greater than Grade 2 abnormalities for low or high sodium (per DAIDS toxicity tables version 2.0 Nov. 2014).
• Any condition that, in the opinion of the investigator, would compromise the safety of the study subject or staff, or would prevent proper conduct of the study.

Sex/Gender

• Sexes Eligible for Study: Male

• Ages: 18 Years to 99 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Guinea, Liberia

Administrative Information

• NCT Number: NCT02818582
• Other Study ID Numbers: 999916137; 16-I-N137
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Responsible Party: National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )
• Study Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: Not Provided

Investigators

• Principal Investigator: Elizabeth S Higgs, M.D.; National Institute of Allergy and Infectious Diseases (NIAID)

• PRS Account: National Institutes of Health Clinical Center (CC)
• Verification Date: October 7, 2019