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Safety and Pharmacokinetics (PK) of Raltegravir in HIV (Human Immunodeficiency Virus)-Infected Children and Adolescents
Phase 1, PHASE2 trial testing Raltegravir poloxamer film coated tablet in HIV Infections in 153 participants. Completed in 18 May 2017.
| Lead sponsor | National Institute of Allergy and Infectious Diseases (NIAID) |
|---|---|
| Phase | Phase 1, PHASE2 |
| Status | Completed |
| Study type | INTERVENTIONAL |
| Allocation | non randomized |
| Design | parallel |
| Masking | none |
| Primary purpose | treatment |
| Enrollment | 153 |
| Start date | 17 September 2007 |
| Primary completion | 3 June 2013 |
| Estimated completion | 18 May 2017 |
| Sites | 42 locations across South Africa, Argentina, Puerto Rico, Botswana, United States, Brazil |
National Institute of Allergy and Infectious Diseases (NIAID)
Adults 30 Days to 18, any sex, with HIV Infections. Patients with the condition only — healthy volunteers not accepted.
Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.
Adverse events were graded using the Division of AIDS (DAIDS) AE Grading Table, Version 1.0. All grade 3 and higher signs, symptoms, and laboratory toxicities were included.
| Group | Value | 95% CI |
|---|---|---|
| Cohort I | 20.3 | 11 – 32.8 |
| Cohort IIA | 25 | 0.6 – 80.6 |
| Cohort IIB | 15.4 | 1.9 – 45.4 |
| Cohort III | 30 | 11.9 – 54.3 |
| Cohort IV | 35.7 | 12.8 – 64.9 |
| Cohort V | 33.3 | 9.9 – 65.1 |
The attribution of relationship of serious adverse events to study drug for the purposes of employing the start, stop and pause rules was by consensus among the site investigator, study team (which includes representatives from Merck) and the Division of AIDS medical officer; if unanimous agreement between them cannot be established, the attribution made by the majority of these 3 persons or entities will be used. Gradation of relationship will use the following terminology: Not related, Probably not related, Possibly related, Probably related or Definitely related.
| Group | Value | 95% CI |
|---|---|---|
| Cohort I | 0 | |
| Cohort IIA | 0 | |
| Cohort IIB | 0 | |
| Cohort III | 0 | |
| Cohort IV | 0 | |
| Cohort V | 0 |
Number of participants who died were summarized.
| Group | Value | 95% CI |
|---|---|---|
| Cohort I | 0 | |
| Cohort IIA | 0 | |
| Cohort IIB | 0 | |
| Cohort III | 0 | |
| Cohort IV | 0 | |
| Cohort V | 0 |
Pharmacokinetic parameters were determined from plasma concentration-time profiles using noncompartmental methods (WinNonlin version 4.01, Pharsight Corp., Mountain View, CA). AUC12h (area-under-the-curve from 0 to 12 hours) were determined using the linear-log trapezoidal rule.
| Group | Value | 95% CI |
|---|---|---|
| Cohort I | 10.2 | ± 10.0 |
| Cohort IIA | 13.4 | ± 16.1 |
| Cohort IIB | 10.5 | ± 3.5 |
| Cohort III | 9.5 | ± 5.5 |
| Cohort IV | 9.3 | ± 3.2 |
| Cohort V | 10.9 | ± 4.4 |
Pharmacokinetic parameters were determined from plasma concentration-time profiles using noncompartmental methods (WinNonlin version 4.01, Pharsight Corp., Mountain View, CA). Maximum plasma concentration (Cmax) was taken directly from the observed concentration-time data.
| Group | Value | 95% CI |
|---|---|---|
| Cohort I | 2813.1 | ± 2673.9 |
| Cohort IIA | 4055.7 | ± 5269.5 |
| Cohort IIB | 5314.2 | ± 2842.6 |
| Cohort III | 5204.8 | ± 2940.6 |
| Cohort IV | 5683.0 | ± 3685.0 |
| Cohort V | 4299.0 | ± 1661.9 |
Pharmacokinetic parameters were determined from plasma concentration-time profiles using noncompartmental methods (WinNonlin version 4.01, Pharsight Corp., Mountain View, CA). Time to half of maximum plasma concentration Cmax (T1/2) was taken directly from the observed concentration-time data.
| Group | Value | 95% CI |
|---|---|---|
| Cohort I | 4.9 | ± 3.6 |
| Cohort IIA | 3.7 | ± 1.4 |
| Cohort IIB | 4.5 | ± 4.2 |
| Cohort III | 4.1 | ± 3.2 |
| Cohort IV | 3.0 | ± 1.8 |
| Cohort V | 2.1 | ± 1.5 |
Pharmacokinetic parameters were determined from plasma concentration-time profiles using noncompartmental methods (WinNonlin version 4.01, Pharsight Corp., Mountain View, CA). Plasma concentration at 12 hours postdose (C12h) was taken directly from the observed concentration-time data.
| Group | Value | 95% CI |
|---|---|---|
| Cohort I | 197.0 | ± 154.2 |
| Cohort IIA | 399.4 | ± 880.9 |
| Cohort IIB | 78.7 | ± 68.9 |
| Cohort III | 39.5 | ± 21.9 |
| Cohort IV | 56.4 | ± 26.8 |
| Cohort V | 99.6 | ± 83.9 |
Adverse events were graded using the Division of AIDS (DAIDS) AE Grading Table, Version 1.0. All grade 3 and higher signs, symptoms, and laboratory toxicities were included.
| Group | Value | 95% CI |
|---|---|---|
| Cohort I | 23.7 | 13.6 – 36.6 |
| Cohort IIA | 25 | 0.6 – 80.6 |
| Cohort IIB | 23.1 | 5 – 53.8 |
| Cohort III | 40 | 19.1 – 63.9 |
| Cohort IV | 42.9 | 17.7 – 71.1 |
| Cohort V | 33.3 | 9.9 – 65.1 |
The attribution of relationship of serious adverse events to study drug for the purposes of employing the start, stop and pause rules was by consensus among the site investigator, study team (which includes representatives from Merck) and the Division of AIDS medical officer; if unanimous agreement between them cannot be established, the attribution made by the majority of these 3 persons or entities will be used. Gradation of relationship will use the following terminology: Not related, Probably not related, Possibly related, Probably related or Definitely related.
| Group | Value | 95% CI |
|---|---|---|
| Cohort I | 0 | |
| Cohort IIA | 0 | |
| Cohort IIB | 0 | |
| Cohort III | 0 | |
| Cohort IV -Data Not Included in This Interim Analysis. | 0 | |
| Cohort V -Data Not Included in This Interim Analysis. | 0 |
Number of participants who died were summarized.
| Group | Value | 95% CI |
|---|---|---|
| Cohort I | 0 | |
| Cohort IIA | 0 | |
| Cohort IIB | 0 | |
| Cohort III | 0 | |
| Cohort IV | 0 | |
| Cohort V | 0 |
Plasma HIV RNA concentrations were determined at entry and at regular intervals using the HIV-1 MONITOR Test, version 1.5 (Roche Molecular Diagnostics) or RealTime HIV-1 (Abbott Molecular), and analyses used the Observed Failure Approach.
| Group | Value | 95% CI |
|---|---|---|
| Cohort I | 72.4 | 59.1 – 83.3 |
| Cohort IIA | 50 | 6.8 – 93.2 |
| Cohort IIB | 76.9 | 46.2 – 95 |
| Cohort III | 70 | 45.7 – 88.1 |
| Cohort IV | 85.7 | 57.2 – 98.2 |
| Cohort V | 100 | 71.5 – 100 |
| Group | Value | 95% CI |
|---|---|---|
| Cohort I | 75 | 61.6 – 85.6 |
| Cohort IIA | 75 | 19.4 – 99.4 |
| Cohort IIB | 90.9 | 58.7 – 99.8 |
| Cohort III | 84.2 | 60.4 – 96.6 |
| Cohort IV | 92.9 | 66.1 – 99.8 |
| Cohort V | 80 | 44.4 – 97.5 |
Change in CD4 cell count from baseline was calculated as the value at later visit minus the value at baseline.
| Group | Value | 95% CI |
|---|---|---|
| Cohort I | 114.6 | 73.9 – 155.4 |
| Cohort IIA | -35.8 | -348.8 – 277.3 |
| Cohort IIB | 143.4 | -12.9 – 299.6 |
| Cohort III | 147.2 | -2.7 – 297.1 |
| Cohort IV | 400.5 | 60.3 – 740.6 |
| Cohort V | 499.2 | -50.4 – 1048.7 |
| Group | Value | 95% CI |
|---|---|---|
| Cohort I | 168.4 | 117.7 – 219.1 |
| Cohort IIA | 189.5 | -154.2 – 533.2 |
| Cohort IIB | 76.8 | -85.3 – 238.9 |
| Cohort III | 158.1 | 11.7 – 304.4 |
| Cohort IV | 278.8 | -185.6 – 743.2 |
| Cohort V | 876.0 | 362.7 – 1389.3 |
Time frame: From study entry to completion of the study at Week 240 or at 14 days after the premature study discontinuation.. Reporting threshold: 1%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.
| Reaction | System | Cohort I | Cohort IIA | Cohort IIB | Cohort III | Cohort IV | Cohort V |
|---|---|---|---|---|---|---|---|
| Pneumonia | Infections and infestations | — | — | — | — | — | — |
| Neutrophil count decreased | Investigations | — | — | — | — | — | — |
| Abdominal pain | Gastrointestinal disorders | — | — | — | — | — | — |
| Pregnancy | Pregnancy, puerperium and perinatal conditions | — | — | — | — | — | — |
| Depression | Psychiatric disorders | — | — | — | — | — | — |
| Neutropenia | Blood and lymphatic system disorders | — | — | — | — | — | — |
| Seizure | Nervous system disorders | — | — | — | — | — | — |
| Suicidal behaviour | Psychiatric disorders | — | — | — | — | — | — |
| Suicidal ideation | Psychiatric disorders | — | — | — | — | — | — |
| Dyspnoea | Respiratory, thoracic and mediastinal disorders | — | — | — | — | — | — |
| Anaemia | Blood and lymphatic system disorders | — | — | — | — | — | — |
| Haemolytic anaemia | Blood and lymphatic system disorders | — | — | — | — | — | — |
| Thrombocytopenia | Blood and lymphatic system disorders | — | — | — | — | — | — |
| Colitis | Gastrointestinal disorders | — | — | — | — | — | — |
| Gastric fistula | Gastrointestinal disorders | — | — | — | — | — | — |
| Gastritis | Gastrointestinal disorders | — | — | — | — | — | — |
| Oesophagitis | Gastrointestinal disorders | — | — | — | — | — | — |
| Pancreatitis | Gastrointestinal disorders | — | — | — | — | — | — |
| Adverse drug reaction | General disorders | — | — | — | — | — | — |
| Pyrexia | General disorders | — | — | — | — | — | — |
| Drug-induced liver injury | Hepatobiliary disorders | — | — | — | — | — | — |
| Hyperbilirubinaemia | Hepatobiliary disorders | — | — | — | — | — | — |
| Abdominal abscess | Infections and infestations | — | — | — | — | — | — |
| Acute sinusitis | Infections and infestations | — | — | — | — | — | — |
| Appendicitis | Infections and infestations | — | — | — | — | — | — |
| Reaction | System | Cohort I | Cohort IIA | Cohort IIB | Cohort III | Cohort IV | Cohort V |
|---|---|---|---|---|---|---|---|
| Cough | Respiratory, thoracic and mediastinal disorders | — | — | — | — | — | — |
| Nasal congestion | Respiratory, thoracic and mediastinal disorders | — | — | — | — | — | — |
| Pyrexia | General disorders | — | — | — | — | — | — |
| Blood sodium decreased | Investigations | — | — | — | — | — | — |
| Headache | Nervous system disorders | — | — | — | — | — | — |
| Oropharyngeal pain | Respiratory, thoracic and mediastinal disorders | — | — | — | — | — | — |
| Rhinorrhoea | Respiratory, thoracic and mediastinal disorders | — | — | — | — | — | — |
| Blood bicarbonate decreased | Investigations | — | — | — | — | — | — |
| Blood glucose decreased | Investigations | — | — | — | — | — | — |
| Vomiting | Gastrointestinal disorders | — | — | — | — | — | — |
| Nausea | Gastrointestinal disorders | — | — | — | — | — | — |
| Alanine aminotransferase increased | Investigations | — | — | — | — | — | — |
| Diarrhoea | Gastrointestinal disorders | — | — | — | — | — | — |
| Neutrophil count decreased | Investigations | — | — | — | — | — | — |
| Aspartate aminotransferase increased | Investigations | — | — | — | — | — | — |
| Blood potassium decreased | Investigations | — | — | — | — | — | — |
| Ear pain | Ear and labyrinth disorders | — | — | — | — | — | — |
| Blood glucose increased | Investigations | — | — | — | — | — | — |
| Blood phosphorus decreased | Investigations | — | — | — | — | — | — |
| Blood bilirubin increased | Investigations | — | — | — | — | — | — |
| Abdominal pain | Gastrointestinal disorders | — | — | — | — | — | — |
| Blood albumin decreased | Investigations | — | — | — | — | — | — |
| Back pain | Musculoskeletal and connective tissue disorders | — | — | — | — | — | — |
| Blood alkaline phosphatase increased | Investigations | — | — | — | — | — | — |
| Wheezing | Respiratory, thoracic and mediastinal disorders | — | — | — | — | — | — |
| Lymphadenopathy | Blood and lymphatic system disorders | — | — | — | — | — | — |
| Impetigo | Infections and infestations | — | — | — | — | — | — |
| Otitis media | Infections and infestations | — | — | — | — | — | — |
| Blood cholesterol increased | Investigations | — | — | — | — | — | — |
| Blood potassium increased | Investigations | — | — | — | — | — | — |
| Haemoglobin decreased | Investigations | — | — | — | — | — | — |
| Lipase increased | Investigations | — | — | — | — | — | — |
| Arthralgia | Musculoskeletal and connective tissue disorders | — | — | — | — | — | — |
| Dizziness | Nervous system disorders | — | — | — | — | — | — |
| Dyspnoea | Respiratory, thoracic and mediastinal disorders | — | — | — | — | — | — |
| Acne | Skin and subcutaneous tissue disorders | — | — | — | — | — | — |
| Pruritus | Skin and subcutaneous tissue disorders | — | — | — | — | — | — |
| Rash | Skin and subcutaneous tissue disorders | — | — | — | — | — | — |
| Ocular hyperaemia | Eye disorders | — | — | — | — | — | — |
| Abdominal pain upper | Gastrointestinal disorders | — | — | — | — | — | — |
Most-reported serious reactions: Pneumonia, Neutrophil count decreased, Abdominal pain, Pregnancy, Depression, Neutropenia, Seizure, Suicidal behaviour.
Data from ClinicalTrials.gov NCT00485264 adverse events section.
Integrase is 1 of 3 HIV (Human Immunodeficiency Virus)-1 enzymes required for viral replication. Raltegravir is a drug that prevents integrase from working properly. This drug has been tested for safety and efficacy in adults, but this is the first study to examine raltegravir in children and adolescents. The purpose of this study was to determine the appropriate dose for raltegravir across the pediatric age range from 4 weeks to 18 years of age, by acquiring short and long term safety data, intensive and population pharmacokinetic (PK) data, and efficacy experience with raltegravir in HIV-infected children and adolescents.
6 peer-reviewed publications reference this trial (live from Europe PMC):
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