E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic nonbacterial osteitis (CNO) in adults |
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E.1.1.1 | Medical condition in easily understood language |
CNO is a chronic musculoskeletal disease, characterized by sterile bone inflammation. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To demonstrate that in CNO patients with pain 3-monthly treatment with pamidronate will result in a significant decrease in maximal pain score (as measured by Brief Pain Inventory (BPI), compared to placebo. |
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E.2.2 | Secondary objectives of the trial |
To study the number of patients with mild pain (>4 on BPI) after 3-monthly treatment with pamidronate, the number of patients with 50% reduction in maximal pain (NRS score in BPI), change in shoulder rating questionnaire (SRQ) and facets of Shoulder function assessment (SFA) score (among which is ability to dress), change in range of motion, improvement in general health as measured with Short Form Health Survey (Sf-36), work activity score , and physical activity, partner burden, change in standard dose of analgesics during course of the study as evidence for efficacy of treatment. Evaluation of confounding factors for outcome of treatment, alteration of inflammation and quantifiable decrease in Na18F-PET/CT tracer uptake of CNO lesions after pamidronate therapy. Evaluation of a possible neuropathic pain and central pain sensitization and association with response. To assess spinal involvement of CNO-lesions, and cost-effectiveness of therapy in an economic evaluation. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Adult patients with an established diagnosis of CNO based on clinical and imaging features. - NRS score for maximal pain of 6/10 or higher at lesion sites* - Signs of disease activity on imaging at lesion sites - No treatment with bisphosphonates for the previous 6 months **
* If the patient uses co-medication possibly targeting CNO-related pain, i.e. paracetamol, NSAIDs, opioids, DMARDs and biologicals on stable dosage, score for maximal pain should be 6/10 or higher despite the use of these medication(s) . Co-medication can be continued throughout the study and will be periodically monitored by the researcher. **For bisphosphonates, a pre-specified wash-out period of 6 months is indicated before inclusion in the study. Biologicals and steroids that are discontinued in a regular care setting (so not continued as co-medication) prior to inclusion in the study also require a pre-specified wash-out period prior to inclusion (as specified in Standard Operating Procedure Washout Periods). |
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E.4 | Principal exclusion criteria |
- Age below 18 years of age - Active pregnancy wish, pregnancy or nursing - Generalized pain without CNO related pain - Bisphosphonate allergy - Estimated glomerular filtration rate < 30 ml/min - Uncontrolled endocrine abnormalities - Active cancer treatment. - Language barrier - Severe co-morbidity, including poor mobility and other causes preventing attendance for control visits - Mental disability NB: In case of poor dental hygiene or inadequate dental care, patients will only be enrolled after oral maxillary surgeon consultation. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change in score of maximal pain on BPI (NRS 0-10) from baseline to 6 months (adjusted for baseline). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Change in range of motion • Number of patients with mild pain (maximal pain as measured with NRS score in BPI ≤4) • Number of patients with 50% reduction in maximal pain (NRS score in BPI) • Change in shoulder rating questionnaire and facets of SFA score (among which are ability to dress) • Change in general health, quality of life, fatigue, work activity score, physical activity, and partner burden • Change in standard dose of analgesics (including NSAIDs) possible during course of the study as evidence for efficacy of treatment. • Evaluation of confounding factors for outcome of treatment such as delay in diagnosis and the amount of baseline tracer uptake, pain and range of motion • Evaluation of a possible neuropathic component of the reported pain • Number of CNO patients exhibiting signs of central sensitization • Association between central sensitization and therapeutic response • Change in biochemical markers of inflammation • Amount of tracer uptake of CNO lesions on Na18F-PET/CT • Spinal involvement • Cost-effectiveness |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Yes |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | No |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
Monitoring disease activity with nuclear imaging |
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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 | Yes |
E.8.1.7.1 | Other trial design description |
After 6 months, the trial continues on an open label basis for pamidronate, which enables crossover |
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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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
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 | No |
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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | |