Trial Outcomes & Findings for Safety and Antiviral Activity of TPV in HCV and/or HBV HIV Coinfected Patients TDM Randomised Pilot Evaluation (NCT NCT00447902)

Last Updated: 2014-05-14

Results Overview

Treatment response is a confirmed virologic response, defined as a viral load less than 50 copies/mL at two consecutive measurements at least 5 days apart, without death, permanent discontinuation, or introduction of a new antiretroviral

Recruitment status

TERMINATED

Study phase

PHASE3

Target enrollment

11 participants

Primary outcome timeframe

48 weeks

Results posted on

2014-05-14

Participant Flow

With FDA and EMEA agreement, the trial was prematurely discontinued before reaching the target number of patients to be entered due to poor recruitment. For this reason analyzing and reporting data as planned for primary and secondary endpoints have not been performed. No objectives were reached and no conclusion can be drawn from this study.

One patient has been randomised by mistake in Brasil and so he was not treated

Participant milestones

Participant milestones
Measure	Standard of Care Tipranavir (TPV) 500mg and Ritonavir (RTV) 200mg BID capsules	Therapeutic Drug Monitoring Tipranavir (TPV) 500mg and Ritonavir (RTV) 200mg BID capsules as initial dose, increased to TPV/r 750mg/200mg BID capsules, or decreased to TPV/r 500mg/100mg BID capsules or TPV/r 250mg/200mg BID capsules
Overall Study STARTED	5	6
Overall Study COMPLETED	1	0
Overall Study NOT COMPLETED	4	6

Reasons for withdrawal

Reasons for withdrawal
Measure	Standard of Care Tipranavir (TPV) 500mg and Ritonavir (RTV) 200mg BID capsules	Therapeutic Drug Monitoring Tipranavir (TPV) 500mg and Ritonavir (RTV) 200mg BID capsules as initial dose, increased to TPV/r 750mg/200mg BID capsules, or decreased to TPV/r 500mg/100mg BID capsules or TPV/r 250mg/200mg BID capsules
Overall Study Adverse Event	0	3
Overall Study Protocol Violation	1	0
Overall Study Withdrawal by Subject	0	1
Overall Study included patients who discontinued	1	1
Overall Study Lack of Efficacy	2	1

Baseline Characteristics

Safety and Antiviral Activity of TPV in HCV and/or HBV HIV Coinfected Patients TDM Randomised Pilot Evaluation

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Standard of Care n=4 Participants Tipranavir (TPV) 500mg and Ritonavir (RTV) 200mg BID capsules	Therapeutic Drug Monitoring n=6 Participants Tipranavir (TPV) 500mg and Ritonavir (RTV) 200mg BID capsules as initial dose, increased to TPV/r 750mg/200mg BID capsules, or decreased to TPV/r 500mg/100mg BID capsules or TPV/r 250mg/200mg BID capsules	Total n=10 Participants Total of all reporting groups
Age, Continuous	46.00 years STANDARD_DEVIATION 2.90 • n=5 Participants	45.20 years STANDARD_DEVIATION 5.40 • n=7 Participants	45.50 years STANDARD_DEVIATION 4.40 • n=5 Participants
Sex: Female, Male Female	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Sex: Female, Male Male	3 Participants n=5 Participants	5 Participants n=7 Participants	8 Participants n=5 Participants

PRIMARY outcome

Timeframe: 48 weeks

Population: The trial has been stopped due to a poor enrollment

Outcome measures

Outcome data not reported

PRIMARY outcome

Timeframe: From the start of the study through 48 weeks.

Dose-limiting hepatotoxicity was defined as Grade 4 ALT or AST elevation confirmed in 48h or any evocative symptoms or signs of hepatitis, if it not clearly attributable to another cause. Patients who experienced dose-limiting hepatotoxicity stopped TPV/r and were considered treatment failures for the analysis.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: After 4 weeks of treatment until the end of the trial

Population: The trial has been stopped due to a poor enrollment

Virologic response defined as viral load less than 50 copies/mL

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 24 and 48 weeks

Population: The trial has been stopped due to a poor enrollment

Patients with a viral load of less than 400 copies/mL at Weeks 24 and 48 as measured from a plasma sample.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: After 4 weeks of treatment until the end of the trial

Patients with a viral load of less than 400 copies/mL at each visit as measured from a plasma sample.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline, 24 and 48 weeks

Population: The trial has been stopped due to a poor enrollment

Occurrence of greater than or equal to 1 log10 drop in viral load from baseline at all visits, including visits at Weeks 24 and 48

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: After 4 weeks of treatment until the end of the trial

Population: The trial has been stopped due to a poor enrollment

Change in viral load (measured from a plasma sample) from baseline at each visitPatients with a viral load of less than 400 copies/mL at each visit as .

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: After Day 1 of treatment until the end of the trial

Population: The trial has been stopped due to a poor enrollment

For patients who never achieve a confirmed virologic response, time to treatment failure is defined as 0. For patients who achieve a confirmed virologic response, time to treatment failure is the earliest time of either: death, permanent discontinuation of the study drug or loss to follow-up, introduction of a new anti-retroviral drug to the regimen if it is not solely related to either toxicity or intolerance clearly attributable to a background drug, but not the study drug, or first occurrence of a VL \>50 copies/mL at two consecutive measurements after having achieved a VL \<50 copies/mL.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: After Day 1 of treatment until the end of the trial

Population: The trial has been stopped due to a poor enrollment

Time to new AIDS or AIDS related progression event or death as defined by AIDS defining and/or AIDS-related illnesses.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: after 2 weeks of treatment till Week 48

Population: The trial has been stopped due to a poor enrollment

Change from baseline to Week 48 for CD4+ and CD8+ cell counts. Samples were obtained for CD4+ and CD8+ as measurements of viral suppression during antiretroviral therapy.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: after 2 weeks of treatment till Week 48

Population: The trial has been stopped due to a poor enrollment

Change from baseline to Week 48 for the ratio of CD38+ to CD8+ cell counts. Samples were obtained for CD38+ and CD8+ as measurements of viral suppression during antiretroviral therapy.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: after 2 weeks of treatment till Week 48

Population: The trial has been stopped due to a poor enrollment

Change from baseline to Week 48 for the ratio of CD3+ CD8+ CD38+ HLA DR . Samples were obtained for CD3+ CD8+ CD38+ HLA DR as measurements of viral suppression during antiretroviral therapy.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: after 2 weeks of treatment till Week 48

Population: The trial has been stopped due to a poor enrollment

Tipranavir (TPV) and Ritonavir (RTV) trough concentrations from plasma samples at Week 2, Week 4, Week 8, Week 12, Week 24, Week 36 and Week 48

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: After 4 weeks of treatment until the end of the trial

Population: The trial has been stopped due to a poor enrollment

number of pills actually taken divided by the planned number of pills the patient should take

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: After 2 weeks of treatment until the end of trial

Population: The trial has been stopped due to a poor enrollment

A high inhibitory quotient (IQ), the ratio of trough plasma drug concentration to the protein-adjusted viral IC50, is a useful indicator of the potential efficacy margin of antiretroviral drugs. The IQ for TPV is calculated by the formula IQ = TPV Ctrough / (3.75 x Z x fold change of the patients virus), where Z = wild type control IC50 IIIB.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: After 2 weeks of treatment until the end of trial

Population: The trial has been stopped due to a poor enrollment

Patients with TPV trough above 120 μM are at high risk of developing a Grade 3 or 4 ALT or AST elevations. The risk of Grade 3 or greater transaminase elevations appeared to be uniform at TPV trough concentration below 120 μM. Hence, for this study the TPV trough should be maintained below 120 μM.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Week 4

Population: The trial has been stopped due to a poor enrollment

Post-dose Tipranavir (TPV) and Ritonavir (RTV) plasma concentrations at Week 4

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline through 48 weeks

Frequency of patients (%) with possible clinically significant abnormalities of laboratory measurements (haematology, differentials (automatic and absolute), coagulation, electrolytes, enzymes, substrates, urinalysis, serology and T-cells)

Outcome measures

Outcome measures
Measure	Standard of Care n=4 Participants Tipranavir (TPV) 500mg and Ritonavir (RTV) 200mg BID capsules	Therapeutic Drug Monitoring n=6 Participants Tipranavir (TPV) 500mg and Ritonavir (RTV) 200mg BID capsules as initial dose, increased to TPV/r 750mg/200mg BID capsules, or decreased to TPV/r 500mg/100mg BID capsules or TPV/r 250mg/200mg BID capsules
Frequency of Patients (%) With Possible Clinically Significant Abnormalities of Laboratory Measurements Hematocrit - decrease	25.0 percentage of participants	16.7 percentage of participants
Frequency of Patients (%) With Possible Clinically Significant Abnormalities of Laboratory Measurements Red Blood Cell count - decrease	25.0 percentage of participants	0 percentage of participants
Frequency of Patients (%) With Possible Clinically Significant Abnormalities of Laboratory Measurements Prothrombin time - increase	0 percentage of participants	20.0 percentage of participants
Frequency of Patients (%) With Possible Clinically Significant Abnormalities of Laboratory Measurements AST/GOT, SGOT - increase	50.0 percentage of participants	33.3 percentage of participants
Frequency of Patients (%) With Possible Clinically Significant Abnormalities of Laboratory Measurements ALT/GPT, SGPT - increase	25.0 percentage of participants	33.3 percentage of participants
Frequency of Patients (%) With Possible Clinically Significant Abnormalities of Laboratory Measurements Lipase - increase	0 percentage of participants	16.7 percentage of participants
Frequency of Patients (%) With Possible Clinically Significant Abnormalities of Laboratory Measurements Bilirubin, total - increase	0 percentage of participants	16.7 percentage of participants
Frequency of Patients (%) With Possible Clinically Significant Abnormalities of Laboratory Measurements Bilirubin, direct - increase	0 percentage of participants	16.7 percentage of participants
Frequency of Patients (%) With Possible Clinically Significant Abnormalities of Laboratory Measurements Triglyceride - increase	0 percentage of participants	25.0 percentage of participants

Adverse Events

Standard of Care

Serious events: 1 serious events

Other events: 3 other events

Deaths: 0 deaths

Therapeutic Drug Monitoring

Serious events: 2 serious events

Other events: 2 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Standard of Care n=4 participants at risk Tipranavir (TPV) 500mg and Ritonavir (RTV) 200mg BID capsules	Therapeutic Drug Monitoring n=6 participants at risk Tipranavir (TPV) 500mg and Ritonavir (RTV) 200mg BID capsules as initial dose, increased to TPV/r 750mg/200mg BID capsules, or decreased to TPV/r 500mg/100mg BID capsules or TPV/r 250mg/200mg BID capsules
General disorders pyrexia	25.0% 1/4 • Screening through the duration of the trial (Week 48 planned).	0.00% 0/6 • Screening through the duration of the trial (Week 48 planned).
Cardiac disorders cardio respiratory arrest	0.00% 0/4 • Screening through the duration of the trial (Week 48 planned).	16.7% 1/6 • Screening through the duration of the trial (Week 48 planned).
Gastrointestinal disorders abdominal pain	0.00% 0/4 • Screening through the duration of the trial (Week 48 planned).	16.7% 1/6 • Screening through the duration of the trial (Week 48 planned).
Gastrointestinal disorders abdominal pain upper	0.00% 0/4 • Screening through the duration of the trial (Week 48 planned).	16.7% 1/6 • Screening through the duration of the trial (Week 48 planned).
Gastrointestinal disorders diarrhoea	0.00% 0/4 • Screening through the duration of the trial (Week 48 planned).	16.7% 1/6 • Screening through the duration of the trial (Week 48 planned).
Gastrointestinal disorders faeces discoloured	0.00% 0/4 • Screening through the duration of the trial (Week 48 planned).	16.7% 1/6 • Screening through the duration of the trial (Week 48 planned).
Gastrointestinal disorders vomiting	0.00% 0/4 • Screening through the duration of the trial (Week 48 planned).	16.7% 1/6 • Screening through the duration of the trial (Week 48 planned).
Hepatobiliary disorders cholelithiasis	0.00% 0/4 • Screening through the duration of the trial (Week 48 planned).	16.7% 1/6 • Screening through the duration of the trial (Week 48 planned).
Investigations aspartate aminotransferase increased	0.00% 0/4 • Screening through the duration of the trial (Week 48 planned).	16.7% 1/6 • Screening through the duration of the trial (Week 48 planned).
Investigations alanine aminotransferase increased	0.00% 0/4 • Screening through the duration of the trial (Week 48 planned).	16.7% 1/6 • Screening through the duration of the trial (Week 48 planned).

Other adverse events

Additional Information

Boehringer Ingelheim Call Center

Boehringer Ingelheim Pharmaceuticals

Phone: 1-800-243-0127

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Any publication of the result of this trial must be consistent with the Boehringer Ingelheim publication policy. The rights of the investigator and of the sponsor with regard to publication of the results of this trial are described in the investigator contract.
Publication restrictions are in place

Restriction type: OTHER

Measure	Standard of Care n=4 participants at risk Tipranavir (TPV) 500mg and Ritonavir (RTV) 200mg BID capsules	Therapeutic Drug Monitoring n=6 participants at risk Tipranavir (TPV) 500mg and Ritonavir (RTV) 200mg BID capsules as initial dose, increased to TPV/r 750mg/200mg BID capsules, or decreased to TPV/r 500mg/100mg BID capsules or TPV/r 250mg/200mg BID capsules
Infections and infestations oral candidiasis	25.0% 1/4 • Screening through the duration of the trial (Week 48 planned).	0.00% 0/6 • Screening through the duration of the trial (Week 48 planned).
Infections and infestations sinusitis	25.0% 1/4 • Screening through the duration of the trial (Week 48 planned).	0.00% 0/6 • Screening through the duration of the trial (Week 48 planned).
Metabolism and nutrition disorders hypertriglyceridaemia	25.0% 1/4 • Screening through the duration of the trial (Week 48 planned).	0.00% 0/6 • Screening through the duration of the trial (Week 48 planned).
Nervous system disorders dizziness	0.00% 0/4 • Screening through the duration of the trial (Week 48 planned).	16.7% 1/6 • Screening through the duration of the trial (Week 48 planned).
Nervous system disorders headache	0.00% 0/4 • Screening through the duration of the trial (Week 48 planned).	16.7% 1/6 • Screening through the duration of the trial (Week 48 planned).
Nervous system disorders paraesthesia	0.00% 0/4 • Screening through the duration of the trial (Week 48 planned).	16.7% 1/6 • Screening through the duration of the trial (Week 48 planned).
Ear and labyrinth disorders vertigo	0.00% 0/4 • Screening through the duration of the trial (Week 48 planned).	16.7% 1/6 • Screening through the duration of the trial (Week 48 planned).
Cardiac disorders palpitations	0.00% 0/4 • Screening through the duration of the trial (Week 48 planned).	16.7% 1/6 • Screening through the duration of the trial (Week 48 planned).
Gastrointestinal disorders abdominal pain	25.0% 1/4 • Screening through the duration of the trial (Week 48 planned).	0.00% 0/6 • Screening through the duration of the trial (Week 48 planned).
Gastrointestinal disorders dysphagia	25.0% 1/4 • Screening through the duration of the trial (Week 48 planned).	0.00% 0/6 • Screening through the duration of the trial (Week 48 planned).
Skin and subcutaneous tissue disorders erythema	0.00% 0/4 • Screening through the duration of the trial (Week 48 planned).	16.7% 1/6 • Screening through the duration of the trial (Week 48 planned).
Musculoskeletal and connective tissue disorders back pain	25.0% 1/4 • Screening through the duration of the trial (Week 48 planned).	0.00% 0/6 • Screening through the duration of the trial (Week 48 planned).
Musculoskeletal and connective tissue disorders muscle spasms	25.0% 1/4 • Screening through the duration of the trial (Week 48 planned).	0.00% 0/6 • Screening through the duration of the trial (Week 48 planned).
Musculoskeletal and connective tissue disorders musculoskeletal pain	25.0% 1/4 • Screening through the duration of the trial (Week 48 planned).	0.00% 0/6 • Screening through the duration of the trial (Week 48 planned).
General disorders adverse drug reaction	50.0% 2/4 • Screening through the duration of the trial (Week 48 planned).	0.00% 0/6 • Screening through the duration of the trial (Week 48 planned).
General disorders pyrexia	25.0% 1/4 • Screening through the duration of the trial (Week 48 planned).	0.00% 0/6 • Screening through the duration of the trial (Week 48 planned).
General disorders fatigue	25.0% 1/4 • Screening through the duration of the trial (Week 48 planned).	0.00% 0/6 • Screening through the duration of the trial (Week 48 planned).
General disorders injection site nodule	25.0% 1/4 • Screening through the duration of the trial (Week 48 planned).	0.00% 0/6 • Screening through the duration of the trial (Week 48 planned).
General disorders nodule	25.0% 1/4 • Screening through the duration of the trial (Week 48 planned).	0.00% 0/6 • Screening through the duration of the trial (Week 48 planned).
Investigations alanine aminotransferase increased	0.00% 0/4 • Screening through the duration of the trial (Week 48 planned).	16.7% 1/6 • Screening through the duration of the trial (Week 48 planned).
Investigations blood albumin decreased	25.0% 1/4 • Screening through the duration of the trial (Week 48 planned).	0.00% 0/6 • Screening through the duration of the trial (Week 48 planned).
Investigations haemoglobin decrease	25.0% 1/4 • Screening through the duration of the trial (Week 48 planned).	0.00% 0/6 • Screening through the duration of the trial (Week 48 planned).
Skin and subcutaneous tissue disorders Skin nodules	25.0% 1/4 • Screening through the duration of the trial (Week 48 planned).	0.00% 0/6 • Screening through the duration of the trial (Week 48 planned).
Investigations aspartate aminotransferase increased	0.00% 0/4 • Screening through the duration of the trial (Week 48 planned).	16.7% 1/6 • Screening through the duration of the trial (Week 48 planned).