E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Human immunodeficiency virus (HIV) infection |
|
E.1.1.1 | Medical condition in easily understood language |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10020161 |
E.1.2 | Term | HIV infection |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
In antiretroviral-naïve, HIV1-infected adults, to compare the effect of a short (14 week) course of oral alendronate 70mg weekly versus placebo combined with calcium and vitamin D, initiated 2 weeks prior to start of antiretroviral therapy (ART) for HIV1 infection on ART-induced bone mineral density (BMD) loss over 48 weeks of follow-up post ART initiation. |
|
E.2.2 | Secondary objectives of the trial |
To explore the effect of alendronate on bone turnover in HIV-1 infected subjects initiating ART. To determine which factors, such as choice of ART, impacts the protective effect of alendronate in preventing BMD loss. To investigate relationships between ART-induced changes in immune function, inflammation, bone metabolism and BMD.
|
|
E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Immunological sub-study (included in the main study protocol Version 1.0, 23rd January 2015). Objective: to explore how changes in T/B cells subset with ART relate to changes in BMD and turnover. Stored PBMC samples will be analysed using polychromatic flow cytometry to evaluate T/B cells and monocyte biomarkers, including markers of immune activation, senescence and cytokine expression, and BTMs will be measured on stored serum samples.
Two analyses will be performed, one at week 14 (week 12 post-ART initiation), when the greatest increases in markers of bone resorption (CTX) are expected, and another at week 50 (week 48 post-ART initiation), when re-establishment of bone remodeling equilibrium is expected to occur.
|
|
E.3 | Principal inclusion criteria |
- male>30 years old or female>40 years old - HIV-1 antibody positive (no CD4 or HIV RNA criteria) - antiretroviral therapy naïve - be presumed to have achieved peak bone mass - eligible for initiation of antiretroviral therapy in the opinion of the investigator - able to provide written informed consent
|
|
E.4 | Principal exclusion criteria |
- Subjects unable to comply with the study protocol or unable to stand/sit upright for at least 30 minutes - history of osteoporosis (defined as hip, femoral neck or spine T score of <-2.5 in men over age >50 or in post-menopausal women) - history of fragility fracture or previous femoral fracture - chronic renal failure estimated by eGFR<60mls/min/1.73m2 at screening using the abbreviated Modification of Diet in Renal Disease (MDRD) equation: - eGFR (ml/min/1,73 m2) = 175 x (CrS) -1,154 x (age)-0,203 x 0,742 (if female) x 1,21 (if black) - hypocalcaemia (corrected calcium <2.2mmol/L) or hypercalcaemia (>2.6mmol/L) at screening - history of Paget’s disease or known primary hyperparathyroidism - previous treatment with or allergy (including hypersensitivity) to bisphosphonates - recent history (past 12 months) of peptic or duodenal ulcers or oesophagitis, aspiration or any other upper gastro-intestinal problem or oesophageal disease that in the opinion of the investigator precludes the use of alendronate - history of dental disease, periodontal disease, poor oral hygiene (as judged in the opinion of the investigator) or recent invasive dental procedures (within the past 3 months) comprising dental extraction and dental prosthetic - current therapy with prescribed calcium or vitamin D preparations (other than over-the-counter multivitamin preparations) - current therapy with aspirin or other regularly prescribed non-steroidal anti-inflammatory drugs - recent significant steroid exposure defined as continual or cumulative use of >5mg prednisolone daily or equivalent for ≥ three months, as per EACS guidelines - for female subjects: pregnancy or breastfeeding at screening, planning future pregnancies or unwilling to take measures to avoid pregnancy for the duration of the study - where in the investigator’s opinion, there is a necessity to initiate ART within the pre-ART study window period (i.e. within the period between screening and ART initiation (approximately 3 weeks) - subjects with active hepatitis B infection (defined as hepatitis B sAg positive) or hepatitis C (defined as hepatitis C Ab and RNA positive) co-infection - any active illness (including AIDS-defining illness) which in the opinion of the investigator precludes participation in the study - cancer or receiving chemotherapy or radiotherapy - subjects concurrently enrolled in another clinical trial of an investigational medical product
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
Between-group difference in percentage change in total hip BMD from baseline to week 50 among subjects who received at least one dose of study medication. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
Between-group differences in percentage change in lumbar spine, femoral neck BMD and body composition to week 50. Between-group differences in percentage change in total hip, lumbar spine and femoral neck BMD to weeks 14 and 26. Between-group differences in percentage change in bone turnover markers to weeks 26 and 50. Between-group differences in percentage change in 25(OH)D, PTH and calcium to week 50. Between-group differences in ART-induced changes immune function, BMD and bone turnover to week 14 and 50. Between-group differences in measures of safety.
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Baseline, week 14, week 26 and week 50 |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |