NCT01199731: SONNET

Dose-finding Study of GSK2248761 in Antiretroviral Therapy-experienced Subjects With NNRTI-resistant HIV Infection

Terminated Phase 2 Results posted Last updated 17 November 2017

What this trial tests

Phase 2 trial testing GSK2248761 100 mg once daily in Infection, Human Immunodeficiency Virus in 30 participants. Terminated before completion.

Timeline

5 October 2010

Primary endpoint
19 July 2011

19 July 2011

Quick facts

Lead sponsor	ViiV Healthcare
Phase	Phase 2
Status	Terminated
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	quadruple
Primary purpose	treatment
Enrollment	30
Start date	5 October 2010
Primary completion	19 July 2011
Estimated completion	19 July 2011
Sites	41 locations across Italy, Belgium, Romania, Canada, United States

Drugs / interventions tested

• GSK2248761 100 mg once daily — full drug profile →
• GSK2248761 200 mg once daily — full drug profile →
• Etravirine (ETRAVIRINE) — full drug profile →

Conditions studied

• Infection, Human Immunodeficiency Virus — all drugs for Infection, Human Immunodeficiency Virus →

Sponsor

ViiV Healthcare — full company profile →

Who can join

18 and older, any sex, with Infection, Human Immunodeficiency Virus. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Percentage of Participants With Human Immunodeficiency Virus Type 1 (HIV-1) Ribonucleic Acid (RNA) <50 Copies Per Milliliter (/mL) at Week 16 Primary · At Week 16

Plasma for quantitative HIV-1 RNA was collected. The percentage of participants with HIV-1 RNA \<50 copies/mL at Week 16 has been presented. A 2 ml plasma was assayed with the real-time NucliSens EasyQ HIV-1 assay (bioMerieux) capable of quantifying as low as 2.5 c/mL by using three modifications to the standard assay: 15 microliters (µl) of extracted eluate, 20 µl of primer, and 5 µl of 2X enzyme in place of standard kit volumes. The validated assay incorporated molecular beacons for detection.

Group	Value	95% CI
ETV 200 mg	33

Number of Participants With Treatment-emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) Secondary · Up to follow-up i.e. 2-4 weeks after the last study visit (due to early termination the last visit was on 19 July 2011)

An AE was defined as any untoward medical occurrence that occurred during the course of the trial after study treatment had started. An adverse event was therefore any unfavorable and unintended sign, symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. An SAE is any untoward medical occurrence that at any dose results in death, are life threatening, requires hospitalization or prolongation of hospitalization or results in disability/incapacity, and congenital anomaly/birth defect.

Any AE

Group	Value	95% CI
GSK2248761 100 mg	7
GSK2248761 200 mg	9
ETV 200 mg	6

Any SAE

Group	Value	95% CI
GSK2248761 100 mg	1
GSK2248761 200 mg	4
ETV 200 mg	0

Number of Participants With Abnormal Clinical Chemistry Laboratory Data With Grade 3 or 4 Treatment-Emergent (TE) Toxicities Secondary · Up to follow-up i.e. 2-4 weeks after the last study visit (due to early termination the last visit was on 19 July 2011)

A toxicity was considered to be TE if it was greater than the Baseline grade, and if it had developed or increased post-Baseline in intensity (and prior to the last dose of IP). Division of acquired immunodeficiency syndrome (AIDS) toxicity scale for Grading the Severity of Adult and Pediatric Adverse Events Version 1.0 was used for grading i.e. Grade 3=severe and Grade 4=potentially life threatening. Categories with values have been presented. No toxicity-related dose reductions of IP was allowed. IP and background antiretroviral therapy (ART) was restarted as soon as medically appropriate; i

Grade 3: Glucose

Group	Value	95% CI
GSK2248761 100 mg	1
GSK2248761 200 mg	0
ETV 200 mg	0

Grade 3: Hyperglycaemia

Group	Value	95% CI
GSK2248761 100 mg	1
GSK2248761 200 mg	0
ETV 200 mg	0

Number of Participants With Abnormal Hematology Laboratory Data With Grade 3 or 4 TE Toxicities Secondary · Up to follow-up i.e. 2-4 weeks after the last study visit (due to early termination the last visit was on 19 July 2011)

A toxicity was considered to be TE if it was greater than the Baseline grade, and if it had developed or increased post-Baseline in intensity (and prior to the last dose of IP). The hematology parameters included hemoglobin, total neutrophils, and white blood cells (WBC) count. Categories with values has been presented. Grade 3=severe and Grade 4=potentially life threatening. No toxicity-related dose reductions of IP was allowed. IP and background ART was restarted as soon as medically appropriate; in general, this was no longer than 14\] days after discontinuation (unless Grade 3 or 4 toxicit

Grade 3: Total Neutrophils

Group	Value	95% CI
GSK2248761 100 mg	1
GSK2248761 200 mg	1
ETV 200 mg	0

Grade 3: WBC

Group	Value	95% CI
GSK2248761 100 mg	0
GSK2248761 200 mg	1
ETV 200 mg	0

Change From Baseline in Plasma HIV-1 RNA Prior to Switch of GSK2248761 Secondary · Baseline (Day 1) and Week 2, 4, 8, 12 and 16

A switch was defined as any ART substitution or addition in the participant's ART regimen. Any ART switch permitted per protocol that was determined necessary and documented prior to the first on-treatment visit where HIV-1 RNA was assessed could occur without penalty. However, any participants with an ART switch not permitted per protocol or ART switch permitted per protocol with a viral load \>=50 copies/mL at the time of the decision to switch was made was counted as a non-responder from that point onward for all assessment windows without a viral load measurement collected prior to the swi

Week 2

Group	Value	95% CI
GSK2248761 100 mg	-1.845	± 0.6029
GSK2248761 200 mg	-2.075	± 0.7070
ETV 200 mg	-1.730	± 1.0923

Week 4

Group	Value	95% CI
GSK2248761 100 mg	-1.985	± 0.6818
GSK2248761 200 mg	-2.621	± 0.5614
ETV 200 mg	-2.064	± 1.2401

Week 8

Group	Value	95% CI
GSK2248761 100 mg	-2.332	± 1.1915
GSK2248761 200 mg	-3.030	± 0.1170
ETV 200 mg	-1.850	± 1.0895

Week 12

Group	Value	95% CI
GSK2248761 100 mg	-1.997	± 0.8918
GSK2248761 200 mg	-3.085	± NA
ETV 200 mg	-1.678	± 1.7096

Week 16

Group	Value	95% CI
ETV 200 mg	-0.820	± 1.6424

Change From Baseline in Plasma HIV-1 RNA After Switch of GSK2248761 Secondary · Baseline (Day 1) and post switch Week 1, 2, 4, withdrawal and follow-up Week 4, 8, 12

A switch was defined as any ART substitution or addition in the participant's ART regimen. Any ART switch permitted per protocol that was determined necessary and documented prior to the first on-treatment visit where HIV-1 RNA was assessed could occur without penalty. However, any participants with an ART switch not permitted per protocol or ART switch permitted per protocol with a viral load \>=50 copies/mL at the time of the decision to switch was made was counted as a non-responder from that point onward for all assessment windows without a viral load measurement collected prior to the swi

Week 1 post switch

Group	Value	95% CI
GSK2248761 100 mg	-2.080	± 1.2175
GSK2248761 200 mg	-2.197	± 1.0203

Week 2 post switch

Group	Value	95% CI
GSK2248761 100 mg	-2.376	± 1.1765
GSK2248761 200 mg	-2.229	± 1.2522

Week 4 post switch

Group	Value	95% CI
GSK2248761 100 mg	-1.617	± 0.8490
GSK2248761 200 mg	-2.545	± 0.6035

Withdrawal

Group	Value	95% CI
GSK2248761 100 mg	-2.070	± 1.4825
GSK2248761 200 mg	-1.978	± 1.5884

4 Week follow-up

Group	Value	95% CI
GSK2248761 100 mg	-2.123	± 1.2717
GSK2248761 200 mg	-1.999	± 1.2019

8 Week follow-up

Group	Value	95% CI
GSK2248761 100 mg	-2.101	± 1.3686
GSK2248761 200 mg	-1.251	± 1.3476

12 Week follow-up

Group	Value	95% CI
GSK2248761 100 mg	0.278	± NA
GSK2248761 200 mg	-2.272	± 0.7077

Number of Participants Who Experienced Disease Progression (HIV-associated Conditions, AIDS and Death) Secondary · Up to follow-up i.e. 2-4 weeks after the last study visit (due to early termination the last visit was on 19 July 2011)

Clinical DP was defined as progression from Baseline HIV disease status:Category A at Baseline to Centers for Disease Control and Prevention(CDC) category B event, category A at Baseline to CDC category C event, category B at Baseline to CDC category C event, category C at Baseline to new CDC category C event or category A, B or C at Baseline to death. Category A consisted of one or more of the conditions like asymptomatic HIV infection, persistent generalized lymphadenopathy and acute (primary) HIV infection with accompanying illness in an adolescent or adult(\>13 years) with documented HIV i

Disease progression

Group	Value	95% CI
GSK2248761 100 mg	0
GSK2248761 200 mg	0
ETV 200 mg	0

Death

Group	Value	95% CI
GSK2248761 100 mg	0
GSK2248761 200 mg	0
ETV 200 mg	0

Absolute Values of CD4+ Cell Counts After Switch of GSK2248761 Secondary · Baseline (Day 1) and post switch Week 1, 2, 4, withdrawal and Follow-up Week 4, 8, 12

CD4 is a receptor for the HIV virus. Most of the damage to an AIDS participant's immune system was done by the virus' destruction of CD4+ lymphocytes. Absolute values of CD4+ cell counts after Switch of GSK2248761 has been presented.

Baseline

Group	Value	95% CI
GSK2248761 100 mg	229.2	± 131.99
GSK2248761 200 mg	162.5	± 108.16

Baseline switch

Group	Value	95% CI
GSK2248761 100 mg	311.0	± 95.11
GSK2248761 200 mg	164.3	± 107.79

Week 1 post switch

Group	Value	95% CI
GSK2248761 100 mg	253.0	± 122.25
GSK2248761 200 mg	189.9	± 132.13

Week 2 post switch

Group	Value	95% CI
GSK2248761 100 mg	263.7	± 112.85
GSK2248761 200 mg	179.0	± 101.59

Week 4 post switch

Group	Value	95% CI
GSK2248761 100 mg	471.5	± 64.35
GSK2248761 200 mg	199.6	± 48.72

Withdrawal

Group	Value	95% CI
GSK2248761 100 mg	254.6	± 137.11
GSK2248761 200 mg	188.5	± 95.30

Week 4 follow-up

Group	Value	95% CI
GSK2248761 100 mg	289.0	± 154.44
GSK2248761 200 mg	237.9	± 110.27

Week 8 follow-up

Group	Value	95% CI
GSK2248761 100 mg	277.5	± 139.41
GSK2248761 200 mg	207.2	± 117.79

Change From Baseline in CD4+ Cell Counts Prior to Switch of GSK2248761 Secondary · Baseline (Day 1) and Week 2, 4, 8, 12 and 16

CD4 is a receptor for the HIV virus. Most of the damage to an AIDS patient's immune system is done by the virus' destruction of CD4+ lymphocytes. Change from Baseline was calculated as (observed value - Baseline value). Baseline was Day 1 value.

Week 2

Group	Value	95% CI
GSK2248761 100 mg	43.0	± 65.74
GSK2248761 200 mg	21.2	± 58.05
ETV 200 mg	62.2	± 81.88

Week 4

Group	Value	95% CI
GSK2248761 100 mg	122.8	± 133.34
GSK2248761 200 mg	60.7	± 79.66
ETV 200 mg	81.4	± 96.88

Week 8

Group	Value	95% CI
GSK2248761 100 mg	76.4	± 111.61
GSK2248761 200 mg	57.3	± 54.29
ETV 200 mg	71.0	± 61.19

Week 12

Group	Value	95% CI
GSK2248761 100 mg	41.0	± 21.21
GSK2248761 200 mg	30.0	± NA
ETV 200 mg	61.5	± 91.53

Week 16

Group	Value	95% CI
ETV 200 mg	-7.0	± 2.00

Change From Baseline in CD4+ Cell Counts After Switch of GSK2248761 Secondary · Baseline (Day 1) and post switch Week 1, 2, 4, withdrawal and Follow-up Week 4, 8, 12

CD4 is a receptor for the HIV virus. Most of the damage to an AIDS patient's immune system is done by the virus' destruction of CD4+ lymphocytes. Change from Baseline was calculated as (observed value - Baseline value). Baseline was Day 1 value.

Week 1 post switch

Group	Value	95% CI
GSK2248761 100 mg	48.2	± 61.10
GSK2248761 200 mg	7.4	± 54.99

Week 2 post switch

Group	Value	95% CI
GSK2248761 100 mg	58.8	± 48.55
GSK2248761 200 mg	4.3	± 42.28

Week 4 post switch

Group	Value	95% CI
GSK2248761 100 mg	74.0	± 62.23
GSK2248761 200 mg	16.6	± 61.59

Withdrawal

Group	Value	95% CI
GSK2248761 100 mg	44.1	± 74.26
GSK2248761 200 mg	26.0	± 71.00

4 Week follow-up

Group	Value	95% CI
GSK2248761 100 mg	59.8	± 56.62
GSK2248761 200 mg	72.0	± 102.38

8 Week follow-up

Group	Value	95% CI
GSK2248761 100 mg	66.3	± 54.09
GSK2248761 200 mg	32.3	± 34.16

12 Week follow-up

Group	Value	95% CI
GSK2248761 200 mg	113.7	± 63.61

Number of Participants Who Discontinued Treatment Due to AEs Secondary · Up to follow-up i.e. 2-4 weeks after the last study visit (due to early termination the last visit was on 19 July 2011)

An AE is defined as any untoward medical occurrence in a participant temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product.

Group	Value	95% CI
GSK2248761 100 mg	0
GSK2248761 200 mg	2
ETV 200 mg	0

Number of Participants With Electrocardiograph (ECG) With Values of Potential Critical Concern (PCI) Secondary · Up to follow-up i.e. 2-4 weeks after the last study visit (due to early termination the last visit was on 19 July 2011)

Number of participants with ECG of PCI above 480 has been presented. ECG was be performed twice on Day 1 at least 5 minutes apart and following 5 minutes of rest in a semi supine position at ∼1 hour prior to first dose. ECG evaluations at other visits was obtained after dosing, preferably at 2 hours post dosing. An ECG machine that automatically calculated the heart rate and measured PR, QRS, QT, and corrected QT (QTc) intervals was used.

Group	Value	95% CI
GSK2248761 100 mg	0
GSK2248761 200 mg	0
ETV 200 mg	0

Adverse events — posted to ClinicalTrials.gov

Time frame: Up to follow-up i.e. 2-4 weeks after the last study visit (due to early termination the last visit was on 19 July 2011). Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

GSK2248761 100 mg

Serious: 1/9 (11%)

Deaths: 0/9

GSK2248761 200 mg

Serious: 4/11 (36%)

Deaths: 0/11

ETV 200 mg

Serious: 0/10 (0%)

Deaths: 0/10

Serious adverse events (3 terms)

Reaction	System	GSK2248761 100 mg	GSK2248761 200 mg	ETV 200 mg
Convulsion	Nervous system disorders	—	—	—
Facial bones fracture	Injury, poisoning and procedural complications	—	—	—
Schizophrenia	Psychiatric disorders	—	—	—

Other adverse events (71 terms — click to expand)

Reaction	System	GSK2248761 100 mg	GSK2248761 200 mg	ETV 200 mg
Sinusitis	Infections and infestations	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—
Insomnia	Psychiatric disorders	—	—	—
Anxiety disorder	Psychiatric disorders	—	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—	—
Muscular weakness	Musculoskeletal and connective tissue disorders	—	—	—
Acute sinusitis	Infections and infestations	—	—	—
Influenza	Infections and infestations	—	—	—
Body tinea	Infections and infestations	—	—	—
Bronchitis	Infections and infestations	—	—	—
Candidiasis	Infections and infestations	—	—	—
Carbuncle	Infections and infestations	—	—	—
Gastroenteritis	Infections and infestations	—	—	—
Pharyngitis	Infections and infestations	—	—	—
Pharyngitis streptococcal	Infections and infestations	—	—	—
Sepsis	Infections and infestations	—	—	—
Upper respiratory tract infection	Infections and infestations	—	—	—
Urinary tract infection	Infections and infestations	—	—	—
Vaginal infection	Infections and infestations	—	—	—
Constipation	Gastrointestinal disorders	—	—	—
Dyspepsia	Gastrointestinal disorders	—	—	—
Dysphagia	Gastrointestinal disorders	—	—	—
Nausea	Gastrointestinal disorders	—	—	—
Paraesthesia oral	Gastrointestinal disorders	—	—	—
Headache	Nervous system disorders	—	—	—
Dizziness	Nervous system disorders	—	—	—
Syncope	Nervous system disorders	—	—	—
Amnesia	Nervous system disorders	—	—	—
Carpal tunnel syndrome	Nervous system disorders	—	—	—
Convulsion	Nervous system disorders	—	—	—
Disturbance in attention	Nervous system disorders	—	—	—
Dysgeusia	Nervous system disorders	—	—	—
Paraesthesia	Nervous system disorders	—	—	—
Parkinsonism	Nervous system disorders	—	—	—
Petit mal epilepsy	Nervous system disorders	—	—	—
Somnolence	Nervous system disorders	—	—	—
Pruritus	Skin and subcutaneous tissue disorders	—	—	—
Eosinophilic pustular folliculitis	Skin and subcutaneous tissue disorders	—	—	—
Night sweats	Skin and subcutaneous tissue disorders	—	—	—
Photosensitivity reaction	Skin and subcutaneous tissue disorders	—	—	—

Most-reported serious reactions: Convulsion, Facial bones fracture, Schizophrenia.

Data from ClinicalTrials.gov NCT01199731 adverse events section.

Sponsor's own description

This 48 week, phase 2b study in 150 HIV-1 infected antiretroviral therapy experienced adult subjects consists of a dose-ranging evaluation of GSK2248761 at blinded doses of 100 mg and 200 mg once daily with a control arm of open-label etravirine (ETV) 200 mg twice daily. The background ART for all three arms will be darunavir/ritonavir (DRV/r) 600 mg/100 mg twice daily plus raltegravir (RAL) 400 mg twice daily. Antiviral activity, safety, PK, and development of viral resistance will be evaluated.

Publications & conference data

1 peer-reviewed publication reference this trial (live from Europe PMC):

1. Non-nucleoside structured compounds with antiviral activity-past 10 years (2010-2020).
   Denel-Bobrowska M, Olejniczak AB. · · 2022 · cited 5× · PMID 35085926 · DOI 10.1016/j.ejmech.2022.114136