Clinical trial NCT04403698
Conditions: Erosive Osteoarthritis
Sponsor: University Hospital, Ghent
Start date: 2019-11-13; Completion date: 2022-03-09
Enrollment: 30 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
It is hypothesized that effervescent alendronate will be able to maintain bone turnover markers within the pre-menopausal reference range and thereby reducing the likelihood of bone turnover associated changes (rebound effect), after discontinuation of denosumab treatment in a non-osteoporotic population.

Detailed description:
Denosumab discontinuation is associated with a rebound effect in bone turnover and loss in bone mass density. These changes resulted in an increase of fracture incidence in patients with postmenopausal osteoporosis back to background levels. However, no excess in fracture incidence was observed. Amongst patients who presented with vertebral fractures after treatment discontinuation, there was a slightly higher incidence of multiple vertebral fractures in patients discontinuing Prolia versus those who discontinued the placebo treatment.

A 2 year, randomized, crossover study demonstrated that alendronate intake after discontinuing denosumab treatment, lead to remaining stable bone mass densitometry (BMD) values in postmenopausal women.

In a study within a non-osteoporotic study population, ongoing at our department, increases in bone turnover are to be expected as soon as patients end study participation (i.e. open label treatment with denosumab, Prolia, anti-RANK ligand inhibition).

It is currently recommended that alternative anti-resorptive therapy may be warranted after Prolia discontinuation. One study describes the use of oral alendronate after denosumab therapy to maintain bone mineral density. However, gastro-intestinal upset and tolerability, as well as difficulty in swallowing pills may limit oral alendronate compliance. To attenuate this concern, buffered soluble (effervescent) alendronate 70 mg, developed with the aim to improve the gastrointestinal tolerability through full dissolution of alendronate in buffered palatable solution before ingestion, will be used.

This study wants to provide a follow up and study wether the use of effervescent alendronate after previous denosumab treatment can prevent a rebound effect in bone turnover that is to be expected when denosumab is discontinued. Subjects that completed our erosive hand osteoarthritis (OA) study and therefore discontinued denosumab 60 mg/every 3 months, will receive alendronate. Moreover, the study wants to asses if there is difference between using alendronate for six or twelve months, starting at the earliest three months but no later than four months after the last injection of denosumab.

Arms: arm 1: Subject receiving alendronate treatment for 24 weeks (n = 20) arm 2: Subject receiving alendronate treatment for 48 weeks (n = 20)
Interventions: intervention 1: Alendronate Effervescent Oral Tablet
Intervention descriptions: intervention 1: At the earliest three months but no later than four months after the last denosumab injection, subjects will be randomized to effervescent alendronate administered for either 24 or 48 weeks

Protocol documents:
Prot_000.pdf: 
The use of Steovess/Binosto after denosumab discontinuation to prevent increase in bone turnover. 
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Study Protocol 
 
 
 
The use of buffered soluble alendronate 70 mg (Steovess/Binosto) 
after denosumab discontinuation to prevent increase in bone 
turnover. 
 
Sponsor/Chief Investigator 
Ghent University Hospital,  
Prof. Dr. Ruth Wittoek, Dept. Of Rheumatology 
Principal Investigator: 
Ruth Wittoek, MD, PhD, Dept. Of Rheumatology – Ghent University Hospital 
Sub-Investigators: 
Dirk Elewaut, MD, PhD Dept. of Rheumatology – Ghent University Hospital 
 
EudraCT number: 2019-003570-11 
Protocolnumber: BC-6072 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Protocol Signature Page  
 
 
Principal/Chief Investigator signature  
 
 
I confirm that I have read and understood protocol version 1.0 dd. 09 August 2019. I agree to 
comply with the study protocol, the principals of GCP, research governance, clinical trial 
regulations and appropriate reporting requirements.  
 
 
 
 
Signature........................................................  Date.......................................  
 
 
 
Print name  ................................................................................................................... 
 
 
 
 
 


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Protocol synopsis  
 
 
Study Type 
Investigator Sponsored Study 
Funder 
Amgen and EffRx Pharmaceuticals 
Study Design 
This is a randomized study to investigate the effect of weekly 70mg effervescent 
alendronate [Steovess 70mg/weekly] on bone turnover after denosumab [Prolia 
60 mg Q3M] discontinuation in patients with erosive osteoarthritis of the 
interphalangeal finger joints.  
At the earliest three months but no later than four months after the last 
denosumab injection, 40 subjects will be randomized to effervescent alendronate 
administered for either 24 (n=20) or  48 weeks (n=20). 
Investigational 
Therapy  
Subjects will be randomized to receive open label effervescent alendronate 
(Steovess/Binosto) for 24 or 48 weeks. All subjects will receive Calcium/vit D 
supplementation. 
Efficacy Objectives 
 
The primary objective of this studyis to investigate if weekly intake of 70mg 
effervescent alendronate can prevent increases in bone turnover above the 
premenopausal reference range at week 48 and if there is difference between using 
alendronate for 24 or 48 weeks, started three months after the last injection of 
denosumab. Other objectives of the study are:  
- 
to assess the changes in bone turnover after 12 and 24 weeks,  
- 
to explore the impact on dual-energy X-ray absorptiometry (DEXA) 
parameters after 24 and 48 weeks of treatment 
- 
to assess radiographic changes and investigate if new erosive joints 
develop at week 24 and 48 
 
 
 
Main Endpoints 
 
The primary endpoint of this objective is to assess the number of patients that 
maintain C-terminal telopeptide of type I collagen (CTx-I) levels within the 
premenopausal reference range at 48 weeks. 
Secondary endpoints are the assessment of the number of patients that maintain 
CTx-I levels within the premenopausal reference range at week 12 and 24 as well 
as the changes in CTx-I and N-terminal propeptide of type I procollagen (P1NP) 
levels from baseline until 12, 24 and 48 weeks after randomization to effervescent 
alendronate.  
Co-exploratory objectives are changes in T-score at lumbar spine and hip from 
baseline to week 24 and week 48, and the radiographic changes at the finger joints 
in terms of new erosive joints and GUSS change between W24 and W48 and 
baseline. 
 
Hypothesis 
The main hypothesis is that effervescent alendronate will be able to maintain 
bone turnover markers within the pre-menopausal reference range, thereby 
reducing the likelihood of bone turnover associated changes. 
Study Sites 
1 site – the UZ Ghent site 
Subjects 
40 subjects for the alendronate follow-up study  
Enrolment 
72 weeks  
Main Eligibility 
Criteria 
Subject must have completed our three year study ‘RANKL-blockade for the 
treatment of erosive osteoarthritis (OA) of interphalangeal finger joints’ 
(EudraCT number: 2015-003223-53; Protocolnumber: AGO/2015/008) 
Study treatment 
Duration 
48 weeks  
 
 


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Table of Contents  
 Protocol Title and Investigators  
 Protocol signature page  
 Protocol synopsis  
 
1. Background and Rationale 
1.1 Disease background   
1.2 Denosumab  
1.3 Effervescent alendronate 
1.4 Rationale for study design 
1.5 Hypotheses 
2. Study Objectives and Endpoints  
3. Experimental Plan 
3.1 Study design and schematic 
3.2 Number of sites  
3.3 Number of subjects 
3.4 Estimated study duration 
3.5 Subject Eligibility 
3.5.1 Inclusion criteria 
3.5.2 Exclusion criteria 
3.6 Criteria for withdrawal 
4. Medication 
4.1 Composition and dosing 
4.2 Producer 
4.3 Distributor 
4.4 Packaging 
4.5 Administration way 
4.6 Labelling: 
4.7 Storage conditions: 
4.8 Known side effects of the medication 
4.9 Drug accountability 
5. Procedures 
5.1 Study procedures 
5.2 Study table 
5.3 Sample processing 
 6. Randomisation 
7. Reporting requirements for investigational product complaints  
8. Concomitant therapy 
9. End of study 
10. Adverse Events/Adverse Event reporting 
10.1. Definitions 
10.2. Adverse Event Reporting 
11. Statistical and Analytical Plans 
11.1 Efficacy analysis 
11.2 Safety analysis 
11.3 Determination of sample size 
12. Quality assurance and periodic monitoring  


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13. Indemnity insurance 
14. Publication Policy 
15. Final Report 
16. Independent Ethics Committee (IEC) / Institutional Review Board (IRB) 
17. Competent Authority  
18. Early termination 
19. Protocol compliance 
20. ICH/GCP guidelines 
21. Subject information and informed consent 
22. Case Report Forms 
23. Direct access to source data / documents 
24. Data handling and record keeping 
25. References 
 
 


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1. Background and Rationale 
 
1.1 Disease background 
 
Prolia (denosumab, anti-RANK ligand therapy) discontinuation is associated with a rebound in 
bone turnover and loss of bone mineral density (BMD).1 These changes resulted in increases of 
fracture incidence in patients with postmenopausal osteoporosis back to background levels, 
however no excess in fracture incidence was observed.2 Amongst the patients that presented 
with vertebral fractures after treatment discontinuation, there was a slightly higher incidence of 
multiple vertebral fractures in patients discontinuing Prolia versus those that discontinued 
placebo.3  
In our study ‘RANKL-blockade for the treatment of erosive hand osteoarthritis (OA) of 
interphalangeal finger joints’ (EudraCT number: 2015-003223-53; Protocolnumber: 
AGO/2015/008) patients are randomized to placebo or denosumab (60 mg/Q3M) for 1 year 
followed by a two-year open label extension in which all subjects receive denosumab (60 
mg/Q3M). Also in this non-osteoporotic population, increases in bone turnover are expected as 
soon as patients end study participation.  
It is currently recommended that other anti-resorptive therapy may be warranted after Prolia 
discontinuation. One study describes the use of oral alendronate after denosumab therapy to 
maintain bone mineral density.4 However, gastro-intestinal upset and tolerability, as well as 
difficulty swallowing pills may limit oral alendronate use. In the current study proposal we 
want to examine the use of effervescent alendronate (Steovess/Binosto) in subjects that 
completed our hand erosive osteoarthritis study and therefore discontinued denosumab 60 
mg/Q3M.We hypothesize that Steovess/Binosto will be able to maintain bone turnover markers 
within the pre-menopausal reference range thereby reducing the likelihood of bone turnover 
associated changes. 
In erosive hand OA, destructive erosive changes, followed by remodelling is key characteristic 
for the disease. As in inflammatory rheumatic diseases, the RANKL pathway appears to be 
involved in the pathogenesis and hence, a therapeutic role of its blockade has been studied in 
the study described above. It is unknown if a potential rebound effect in bone turnover might 
also be associated with a rebound in erosive destructive progression at the subchondral bone. 
 
1.2 Denosumab 
Denosumab (Amgen), is a fully human monoclonal antibody designed to inhibit RANKL 
(RANK Ligand). RANKL binds to RANK, which exists as a cell surface receptor molecule on 
“pre”-osteoclasts: precursors of osteoclasts.  
Binding of RANKL to RANK acts as the primary signal for bone removal in normal 
physiological bone remodeling and in a number of pathological conditions, e.g. malignant 
tumors and bone metastasis.   
Activation of RANK by RANKL promotes the maturation of pre-osteoclasts into osteoclasts. 
Denosumab inhibits osteoclasts’ maturation, function and survival by binding to and inhibiting 


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RANKL. This mimics the natural action of osteoprotegerin, an endogenous RANKL inhibitor 
that presents with decreasing concentrations in patients who are suffering from osteoporosis. 
This protects bone from degradation, and helps to counter the progression of the disease.  
Denosumab was approved by the EMA for use in postmenopausal women with osteoporosis at 
increased risk for fracture at the dose of 60 mg sc every 6 months (Prolia), and for the prevention 
of skeletal-related events in patients with bone metastasis from solid tumors at the dose of 120 
mg every 4 weeks (XGEVA). 
More recently, denosumab was shown to retard the progression of structural lesions in 
rheumatoid arthritis, an unapproved indication for the drug.5,6 Its dosing and safety profile 
depended on the different medical conditions in which the drug was used. Patients with 
osteoporosis and rheumatoid arthritis received 60 mg and up to 180 mg injected SC, every 6 
months, respectively.  
Experience from clinical studies indicates that side effects depend on the dosage.  
According to Prolia Summary of Product Characteristics (SmPC)7, pain in extremities and 
musculoskeletal pain (including back pain and joint pain) were among the most common 
adverse reactions. 
In patients treated for osteoporosis a rare unwanted effect included low calcium levels, 
especially when in case of an impaired kidney function. Patients must therefore be adequately 
supplemented with calcium and vitamin D levels before starting and during denosumab therapy. 
In the postmarketing setting, rare cases of severe symptomatic hypocalcaemia have been 
reported. Clinical monitoring of calcium level is recommended before each dose and, in patients 
predisposed to hypocalcaemia, within two weeks after the initial dose. 
There have been rare cases of atypical femoral fracture reported in association with Prolia. 
Infections of the urinary and respiratory tracts were reported as well as cellulitis, ear infection 
and diverticulitis.  The SmPC includes a Warning Statement regarding skin infections 
(predominantly cellulitis) leading to hospitalization. It has been proposed that this increase in 
infections under denosumab treatment might be connected to the role of RANKL in the immune 
system.  
Cataracts, constipation, skin rashes and eczema were also seen. 
Osteonecrosis of the jaw (ONJ) was reported rarely in Prolia osteoporosis clinical development 
program. Primarily, at the high dosages used in patients with bone metastases, similarly to 
bisphosphonates, denosumab appeared to be implicated in increasing the risk of osteonecrosis 
of the jaw (ONJ) especially following extraction of teeth or oral surgical procedures. 
In the post-marketing setting, rare events of drug-related hypersensitivity, including rash, 
urticaria, facial swelling, erythema, and anaphylactic reactions have been reported. 
In the FREEDOM extension study8,9, with up to 8 years of denosumab 60 mg Q6M exposure, 
the incidence rates of adverse events did not increase over time.  
Denosumab safety data were reported  in RA phase 2 studies5,6. The safety profile appears to 
be consistent with that in patients with postmenopausal osteoporosis. Denosumab did not have 
an effect on RA disease activity, as measured by the ACR response criteria, the DAS28 scores, 


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and the occurrence of RA flares. 
 
1.3 Effervescent alendronate (Steovess/Binosto) 
Bisphosphonates are widely used to prevent or to treat osteoporosis via inducing osteoclast 
apoptosis and inhibiting bone resorption.10  In particular, alendronate has been reported to be 
an effective and well-tolerated drug for prevention and treatment of osteoporosis, offering 
sustained treatment benefits up to 2 years,  with respect to increased BMD11,12 and up to 4 years 
in terms of fracture prevention13,14,15. Alendronate, a second generation bisphosphonate, inhibits 
osteoclast activity, reduces bone resorption, and maintains the balance of bone resorption and 
formation.16,17  Alendronate may also stimulate osteoblast differentiation, and prevent or 
mitigate bone cell and osteoblast apoptosis.18,19 
A recent systemic review and meta-analysis including 1002 patients 20 on the use of alendronate 
in glucocorticoid-induced osteoporosis concluded that alendronate treatment significantly 
increased BMD of the lumbar spine and femoral neck during 6 to 24 months. These beneficial 
effects were apparent at 12 months after treatment for the lumbar spine but not the femoral neck 
BMD. Alendronate treatment did not significantly seem to change fracture risk. However, as 
relatively insufficient data regarding the fracture incidence has been reported, more research 
need to be carried out to determine the efficacy of alendronate in the prevention of fracture.  
The most common adverse reactions21  (incidence greater than or equal to 3%) are abdominal 
pain, acid regurgitation, constipation, diarrhea, dyspepsia, musculoskeletal pain, and nausea.  
Bisphosphonates administered orally, may cause local irritation of the upper gastrointestinal 
mucosa. Because of these possible irritant effects and a potential for worsening of the 
underlying disease, caution should be used when alendronate is given to patients with active 
upper gastrointestinal problems (such as known Barrett's esophagus, dysphagia, other 
esophageal diseases, gastritis, duodenitis, or ulcers). Esophageal adverse experiences, such as 
esophagitis, esophageal ulcers and esophageal erosions, occasionally with bleeding and rarely 
followed by esophageal stricture or perforation, have been reported in patients receiving 
treatment with oral bisphosphonates including alendronate sodium. In some cases these have 
been severe and required hospitalization. 
Hypocalcemia must be corrected before initiating therapy with alendronate. Other disorders 
affecting mineral metabolism (such as vitamin D deficiency) should also be effectively 
treated. In patients with these conditions, serum calcium and symptoms of hypocalcemia 
should be monitored during therapy with alendronate. Presumably due to the effects of 
alendronate on increasing bone mineral, small, asymptomatic decreases in serum calcium 
and phosphate may occur. Patients should receive adequate calcium and vitamin D intake.  
Osteonecrosis of the jaw (ONJ), which can occur spontaneously, is generally associated with 
tooth extraction and/or local infection with delayed healing, and has been reported in patients 
taking bisphosphonates, including alendronate sodium. Known risk factors for osteonecrosis of 
the jaw include invasive dental procedures (e.g., tooth extraction, dental implants, boney 
surgery), diagnosis of cancer, concomitant therapies (e.g., chemotherapy, corticosteroids, 
angiogenesis inhibitors), poor oral hygiene, and co-morbid disorders (e.g., periodontal and/or 


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other pre-existing dental disease, anemia, coagulopathy, infection, ill-fitting dentures). The risk 
of ONJ may increase with duration of exposure to bisphosphonates.  For patients requiring 
invasive dental procedures, discontinuation of bisphosphonate treatment may reduce the risk 
for ONJ. Clinical judgment of the treating physician and/or oral surgeon should guide the 
management plan of each patient based on individual benefit/risk assessment. 
Atypical, low-energy, or low trauma fractures of the femoral shaft have been reported in 
bisphosphonate-treated patients. These fractures can occur anywhere in the femoral shaft from 
just below the lesser trochanter to above the supracondylar flare and are transverse or short 
oblique in orientation without evidence of comminution. Causality has not been established 
as these fractures also occur in osteoporotic patients who have not been treated with 
bisphosphonates. Atypical femur fractures most commonly occur with minimal or no trauma 
to the affected area. They may be bilateral and many patients report prodromal pain in the 
affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete 
fracture occurs. A number of reports note that patients were also receiving treatment with 
glucocorticoids (e.g., prednisone) at the time of fracture. Any patient with a history of 
bisphosphonate exposure who presents with thigh or groin pain should be suspected of having 
an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Patients 
presenting with an atypical fracture should also be assessed for symptoms and signs of fracture 
in the contralateral limb. Interruption of bisphosphonate therapy should be considered, 
pending a risk/benefit assessment, on an individual basis. 
 
1.4 Rationale for study design  
Denosumab discontinuation is associated with a rebound in bone turnover and loss of BMD1. 
These changes resulted in an increase of fracture incidence in patients with postmenopausal 
osteoporosis back to background levels. However, no excess in fracture incidence was 
observed2. Amongst the patients who presented with vertebral fractures after treatment 
discontinuation, there was a slightly higher incidence of multiple vertebral fractures in patients 
discontinuing Prolia versus those who discontinued the placebo treatment3.  
A 2 year, randomized, crossover study demonstrated that alendronate intake after discontinuing 
denosumab treatment, lead to remaining stable BMD-values in postmenopausal women4.  
Also in the study with non-osteoporotic study population, ongoing in our department, increases 
in bone turnover are expected as soon as patients end study participation.  
It is currently recommended that other anti-resorptive therapy may be warranted after Prolia 
discontinuation. One study describes the use of oral alendronate after denosumab therapy to 
maintain bone mineral density4. However, gastro-intestinal upset and tolerability, as well as 
difficulty swallowing pills may limit oral alendronate use, therefore possibly compromising 
patients adherence. To attenuate this concern, buffered soluble (effervescent) alendronate 70 
mg will be used which was developed with the aim to improve the GI tolerability through full 
dissolution of alendronate in buffered palatable solution before ingestion22.  
 
This study wants to provide a follow up and examine the use of effervescent alendronate  after 
denosumab treatment.  Subjects that completed our erosive hand OA study and therefore 


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discontinued denosumab 60 mg/Q3M, will receive alendronate.  Moreover, the study wants to 
asses if there is difference between using alendronate for six or twelve months, starting at the 
earliest three months but no later than four months after the last injection of denosumab. 
1.5 Hypotheses 
It is hypothesized that effervescent alendronate will be able to maintain bone turnover markers 
within the pre-menopausal reference range thereby reducing the likelihood of bone turnover 
associated changes, after discontinuation of Prolia treatment in a non-osteoporotic population. 
 
 
2. Study Objectives and Endpoints 
 
The objectives of the effervescent alendronate treatment after denosumab discontinuation are 
to investigate if weekly intake of effervescent alendronate can prevent increases in bone 
turnover above the premenopausal reference range* at week 48 and if there is difference 
between using alendronate for 24 or 48 weeks, started at the earliest three months but no later 
than four months after the last injection of denosumab.  
* Reference range: CTX-I (IVD kit) Non menopausal women < 700ng/l. Menopausal women < 730ng/l. Adult male >20 to 
120 years: < 695ng/L ; P1NP (IVD kit): Male > 45 years: 12.8-71.9 µg/L Non menopausal women: 13.7-71.1 µg/L 
Menopausal women: < 82.6 µg/L 
Other objectives of the study are:  
- 
to assess the changes in bone turnover after 12 and 24 weeks,  
- 
to explore the impact on dual-energy X-ray absorptiometry (DEXA) parameters after 24 and 48 weeks of 
treatment 
- 
to assess radiographic changes and investigate if new erosive joints develop at week 24 and 48 
 
The primary endpoint of this objective is  the number of patients that maintain C-terminal 
telopeptide of type I collagen (CTx-I) within the premenopausal reference range at 48 weeks. 
Secondary endpoints are the  number of patients that maintain CTx-I within the 
premenopausal reference range at week 12 and 24 as well as the changes in CTx-I and N-
terminal propeptide of type I procollagen (P1NP) from baseline until 12, 24 and 48 weeks 
after randomization to effervescent alendronate. 
Co-exploratory objectives are changes in T-score at lumbar spine and hip from baseline to week 24 
and week 48, and related to the underlying erosive hand OA disease, the radiographic changes at the 
finger joints in terms of new (radiographic) erosive joints (n) and GUSS change (∆) between W24 and 
W48 and baseline. 
 
Safety-objective 
This study will assess the safety of the weekly administration of effervescent alendronate 70mg 
in the population of patients with erosive OA. Safety evaluations will be made by recording the 
incidence of AE/SAE 
 


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3. Experimental Plan  
 
3.1  Study design and schematic 
This is a randomized study to investigate the effect of effervescent alendronate on BTM after 
denosumab discontinuation.  
At the earliest three months but no later than four months after the last denosumab injection, 40 
subjects will be randomized to effervescent alendronate administered for either 24 (n=20) or  
48 weeks (n=20). The randomization code will be generated by a randomization manager. 
Randomization will be done in blocks of four. 
Study schematic 
 
 
 
 
 
 
 
 
 
 
3.2 Number of sites  
The study will be conducted in one site – the UZ Ghent site in Belgium. 
 
 
3.3 Number of subjects 
Forty subjects, having finished the denosumab study, will be recruited within an enrolment 
period of 72 weeks. 
 
 
3.4 Estimated study duration 
The total treatment duration per subject is 48 weeks. The expected total trial duration 
defined as the time from first patient first visit to last patient last visit is 125 weeks.   
 
 
 
 
 
W12 
W24 
W48 
n = 20 
n = 20 
RANDOMISATION 
END OF DENOSUMAB TRIAL 
N = 40 
BASELINE 
END OF STUDY 
alendronate 70mg/QW  
alendronate 70mg/QW  
alendronate 70mg/QW  
Stop medication, follow up   
48 Weeks 
Ca & Vit D 


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3.5 Subject eligibility 
 
3.5.1 
Inclusion criteria 
A subject will be eligible for study participation if he/she meets the following criteria: 
 
Subjects must have completed the 48 weeks of the randomised placebo-controlled 
study phase followed by the 96 weeks open label denosumab 60 mg SC every 3 months 
phase. (EudraCT number: 2015-003223-53) 
 
Last denosumab injection less than four months ago 
 
Able and willing to give written informed consent and to comply with the requirements 
of the study protocol 
 
3.5.2 
Exclusion criteria 
A subject will be excluded from the study if he/she meets any of the following criteria:  
 Patients with clinically significant hypersensitivity to any of the components of 
effervescent alendronate. 
 Patient who is pregnant or planning pregnancy 
 Female subjects who are breast-feeding. 
 History of osteonecrosis of the jaw, and/or recent (within 3 months) tooth extraction 
or other unhealed dental surgery; or planned invasive dental work during the study  
 Subject has any kind of disorder that compromises the ability of the subject to give 
written informed consent and/or to comply with study procedures 
 Hypocalcaemia. 
 Oesophageal disease, gastritis, duodenitis, ulcers, or with a recent history (within the 
previous year) of major gastro-intestinal disease such as peptic ulcer, or active gastro-
intestinal bleeding, or surgery of the upper gastro-intestinal tract other than 
pyloroplasty. 
 Abnormalities of the oesophagus and other factors which delay oesophageal emptying 
such as stricture or achalasia. 
 Inability to stand or sit upright for at least 30 minutes. 
 
 
3.6 Criteria for withdrawal 
Subjects may prematurely discontinue from the study at any time. Premature discontinuation 
from the study is to be understood when the subject did not undergo end of study examination. 
Subjects can be withdrawn under the following circumstances: 
 at their own request 
 if the investigator feels it would not be in the best interest of the subject to continue 
 if the subject violates conditions laid out in the informed consent form or disregards 
instructions by the clinical investigation personal 
 in case the subject experiences an adverse event due to the investigational product 
 


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In all cases, the reason why subjects are withdrawn must be recorded in detail in the CRF and 
in the subject’s medical records.  
 
4. Medication (see also paragraph 1.3) 
  
4.1. Composition and dosing 
After denosumab discontinuation subjects will be randomized to receive open label effervescent 
alendronate (Steovess) for 24 or 48 weeks. Effervescent alendronate a bisphosphonate as 
effervescent tablets that should be taken once a week. Each effervescent tablet contains 70 mg 
alendronic acid as 91.37 mg of alendronate sodium trihydrate. Excipients are sodium 
dihydrogen citrate, citric acid anhydrous, sodium hydrogen carbonate, sodium carbonate 
anhydrous, strawberry flavour [Maltodextrin (Maize), arabic gum, propylene glycol (E 1520), 
nature-identical flavouringsubstances], acesulfame potassium and sucralose. Each tablet 
contains 602.54 mg of sodium. Effervescent alendronate is supplied as a white to off-white 
round effervescent tablets of 25 mm diameter, flat faced with bevelled edges.  
4.2. Producer 
Steovess/Binosto is manufactured by Temmler Pharma GmbH - Temmlerstraße 2 - 35039 
Marburg - Germany  
4.3. Distributor  
Steovess is released in the EU by Laboratoires Expanscience, Paris, France.  
4.4. Packaging 
The effervescent tablets are provided in strips of composite foil with effervescent 2 tablets 
packed in individual units per strip and packed with 4 or 12 tablets per box.  
4.5. Administration way 
Effervescent alendronate 70 mg should only be taken upon arising for the day dissolved in half 
a glass of plain water (not less than 120 ml or 4.2 fl.oz.). Dissolving the tablet in water yields a 
buffered solution of pH 4.8 – 5.4. The buffered solution should be drunk, once the fizzing has 
subsided and the effervescent tablet has completely dissolved to give a clear, colourless, 
buffered solution, followed by at least 30 ml (one sixth of a glass) of plain water. Additional 
plain water may be taken. Patients should not swallow the undissolved effervescent tablet, 
should not chew the effervescent tablet or allow the effervescent tablet to dissolve in their 
mouths because of the risk for oropharyngeal irritation. Patients should not lie down for at least 
30 minutes after taking effervescent alendronate 70 mg. 
Steovess will be distributed during study visits. Subjects should take one 70 mg effervescent 
tablet once weekly at home. Patients should be instructed that if they miss a dose of alendronate 
70 mg, they should take one effervescent tablet on the morning after they remember. They 
should not take two effervescent tablets on the same day but should return to taking one 
effervescent tablet once a week, as originally scheduled on their chosen day. 


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Alendronate 70 mg must be taken at least 30 minutes before the first food, beverage, or 
medicinal product of the day with plain water only. Other beverages (including mineral water), 
food and some medicinal products are likely to reduce the absorption of alendronate.  
Patients are requested not to take any study medication on the morning of a planned visit (week 
12, week 24 or week 48): this accounts for the study medication (Steovess) and the calcium/ 
vitamine D supplements. 
 
4.6. Labelling 
The open-label STEOVESS will be delivered by Laboratoires Expanscience to the Ghent 
University Hospital Department of Rheumatology (via the Ghent University Hospital 
Pharmacy). All packages will be labeled study-specific following EU GMP guidelines and the 
hospital law by the Ghent University Hospital Pharmacy before dispensing to the subjects. 
Example of the label can be found in annex I 
 
4.7. Storage conditions 
This medicinal product does not require any special temperature storage conditions. Store in 
the original package in order to protect from moisture.  
 
4.8. Known side effects of the medication 
Clinical Trials Experience  
Because clinical trials are conducted under widely varying conditions, adverse reaction rates 
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials 
of another drug and may not reflect the rates observed in clinical practice.  
The safety of BINOSTO (alendronate sodium) effervescent tablet 70 mg is based on clinical 
trial data of alendronate sodium 10 mg daily and alendronate sodium 70 mg weekly.  
Treatment of Osteoporosis in Postmenopausal Women  
Daily Dosing The safety of alendronate sodium 10 mg daily in the treatment of postmenopausal 
osteoporosis was assessed in four clinical trials that enrolled 7453 women aged 44-84 years. 
Study 1 and Study 2 were identically designed, three-year, placebo-controlled, double-blind, 
multicenter studies (United States and Multinational n=994); Study 3 was the three year 
vertebral fracture cohort of the Fracture Intervention Trial [FIT] (n=2027) and Study 4 was the 
four-year clinical fracture cohort of FIT (n=4432). Overall, 3620 patients were exposed to 
placebo and 3432 patients exposed to alendronate. Patients with pre-existing gastrointestinal 
disease and concomitant use of non-steroidal anti-inflammatory drugs were included in these 
clinical trials. In Study 1 and Study 2 all women received 500 mg elemental calcium as 
carbonate. In Study 3 and Study 4 all women with dietary calcium intake less than 1000 mg per 
day received 500 mg calcium and 250 IU Vitamin D per day.  
Among patients treated with alendronate 10 mg or placebo in Study 1 and Study 2, and all 
patients in Study 3 and Study 4, the incidence of all-cause mortality was 1.8% in the placebo 
group and 1.8% in the alendronate group. The incidence of serious adverse events was 30.7% 
in the placebo group and 30.9% in the alendronate group. The percentage of patients who 
discontinued the study due to any clinical adverse event was 9.5% in the placebo group and 


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8.9% in the alendronate group. Adverse reactions from these studies considered by the 
investigators as possibly, probably, or definitely drug related in greater than or equal to 1% of 
patients treated with either alendronate or placebo are presented in Table 1 
Rarely, rash and erythema have occurred. 
 
Gastrointestinal Adverse Reactions: One patient treated with alendronate sodium (10 mg/day), 
who had a history of peptic ulcer disease and gastrectomy and who was taking concomitant 
aspirin developed an anastomotic ulcer with mild hemorrhage, which was considered drug 
related. Aspirin and alendronate sodium were discontinued and the patient recovered. In the 
Study 1 and Study 2 populations, 49-54% had a history of gastrointestinal disorders at baseline 
and 54-89% used nonsteroidal anti-inflammatory drugs or aspirin at some time during the 
studies . 
 
Laboratory Test Findings: In double-blind, multicenter, controlled studies, asymptomatic, 
mild, and transient decreases in serum calcium and phosphate were observed in 
approximately 18% and 10%, respectively, of patients taking alendronate versus 
approximately 12% and 3% of those taking placebo. However, the incidences of decreases in 
serum calcium to less than 8.0 mg/dL (2.0 mM) and serum phosphate to less than or equal to 
2.0 mg/dL (0.65 mM) were similar in both treatment groups.  
Weekly Dosing The safety of alendronate sodium 70 mg once weekly for the treatment of 
postmenopausal osteoporosis was assessed in a one-year, double-blind, multicenter study 
comparing alendronate 70 mg once weekly and alendronate 10 mg daily. The overall safety and 


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tolerability profiles of once weekly alendronate 70 mg and alendronate 10 mg daily were 
similar. The adverse reactions considered by the investigators as possibly, probably, or 
definitely drug related in greater than or equal to 1% of patients in either treatment group are 
presented in Table 2.  
 
Osteoporosis in Men  
In two placebo-controlled, double-blind, multicenter studies in men (a two-year study of 
alendronate sodium 10 mg/day and a one-year study of once weekly alendronate sodium 70 
mg) the rates of discontinuation of therapy due to any clinical adverse event were 2.7% for 
alendronate 10 mg/day vs. 10.5% for placebo, and 6.4% for once weekly alendronate 70 mg vs. 
8.6% for placebo. The adverse reactions considered by the investigators as possibly, probably, 
or definitely drug related in greater than or equal to 2% of patients treated with either 
alendronate or placebo are presented in the following table. 
 
Post-Marketing Experience  
The following adverse reactions have been identified during post-approval use of alendronate 
sodium. Because these reactions are reported voluntarily from a population of uncertain size, it 


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is not always possible to reliably estimate their frequency or establish a causal relationship to 
drug exposure.  
Body as a Whole: hypersensitivity reactions including urticaria and angioedema. Transient 
symptoms of myalgia, malaise, asthenia and fever have been reported with alendronate, 
typically in association with initiation of treatment. Symptomatic hypocalcemia has occurred, 
generally in association with predisposing conditions. Peripheral edema.  
Gastro intestinal: esophagitis, esophageal erosions, esophageal ulcers, esophageal stricture or 
perforation, and oropharyngeal ulceration. Gastric or duodenal ulcers, some severe and with 
complications have also been reported 
Dental: Localized osteonecrosis of the jaw, generally associated with tooth extraction 
and/or local infection with delayed healing, has been reported.  
Musculoskeletal: bone, joint, and/or muscle pain, occasionally severe and incapacitating ;joint 
swelling; low-energy femoral shaft and subtrochanteric fractures  
Nervous system: dizziness and vertigo.  
Pulmonary: acute asthma exacerbations  
Skin: rash (occasionally with photosensitivity), pruritus, alopecia, severe skin reactions, 
including Stevens-Johnson syndrome and toxic epidermal necrolysis.  
Special Senses: uveitis, scleritis or episcleritis. Cholesteatoma of the external auditory canal 
(focal osteonecrosis). 
 
4.9. Drug accountability 
The arrival of the study medication at the hospital pharmacy and the delivery to the study site 
(Department of Rheumatology) will be documented. Drug accountability will be documented 
with the description of the batch number, expiration date and date distributed to the subject. 
Patients are requested to keep a medication log which contains the day and time of the 
administration. 
 
5. Procedures 
 
5.1 Study procedures  
A screening visit will include explanation and signing of the informed consent form and 
overview of in- and exclusion criteria in order to participate. If appropriate, a pregnancy test 
will be performed.  
The maximum window allowed between the screening visit and the baseline visit is of 3 weeks. 
Upon selection, patients will be included in the study during the baseline visit, which will 
include completion of NRS pain, a hand radiograph, Dual energy X-ray absorptiometry (DXA) 
and the laboratory investigations required. These will comprise a calcium and vitamin D status, 
kidney function tests (serum ureum, serum creatinine, GFR), bone turnover markers (BTM), 
and, if appropriate, a pregnancy test.  A maximum of 45 ml of blood will be collected each visit. 


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Patients will be randomized to alendronate for 24 weeks or 48 weeks: study products (Steovess, 
alendronate 70mg every week) will then be provided to the patient. Calcium/Vit D 
supplementation will be installed.  
Schedule of assessments are provided in detail as Appendix 1. Safety assessment is clarified in 
the safety paragraph. 
At week 12: safety assessment NRS pain, BTM 
At week 24: safety assessment, NRS pain, serum calcium levels and BTM, hand radiographs 
and DXA 
At week 48: safety assessment, NRS pain, hand radiographs, DXA and the laboratory 
investigations required.These will comprise a calcium and vitamin D status, kidney function 
tests (serum ureum, serum creatinine, GFR), and BTM.  
Safety: Patients will be able to report any unwanted effect during the regular visits and through 
telephone contact at any time in between these visits. Templates for AE/SAE recording created 
by the sponsor will be used. 
 
A negative pregnancy test will be an entry requirement in female premenopausal patients. 
Premenopausal patients at risk to become pregnant will be excluded if no valid anti-conceptive 
method is used. In practice, premenopausal women will be an absolute minority in this study 
population. All through the time of the study pregnancy tests will be done during the visits. 
 
5.2 Study table 
 
 
Distribution 
IMP 
Safety 
Laboratory1 
CR 
hand 
DXA 
NRS 
pain 
 
Kidney 
function BTM Vit D Ca++ 
Preg. 
test* 
 
SCREENING
/ BASELINE 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
WEEK 12 
(+/- 7 days) 
X 
X 
 
X 
 
 
X 
 
 
X 
WEEK 24 
(+/- 7 days) 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
WEEK 48 
(+/- 7 days) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
* if 
appropriate 
 
 
 
 


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Kidney function tests including serum creatinine, ureum and glomerular filtration rate (GFR). 
Depending on the individual patient, additional parameters may be added.  
1 Samples must be obtained following an overnight fast during the morning. 
 
5.3 Sample processing 
Blood samples collected during the visits will be used for clinical analysis.  
At baseline visit, W12, W24 and W48 three extra serum tubes will be collected. After 
centrifugation (4000 RT/10min) the serum will be allocated in vials of 1ml and stored at -80°C.  
At the end of the study those samples will be send to an external lab for analysis of the BTM. 
 
6. Randomisation 
The randomization code will be generated by a randomization manager. Randomization will be 
done in blocks of four. 
 
 
7. Reporting requirements for investigational product complaints  
The following could be considered potential product complaints that need to be reported to 
EffRx Pharmaceuticals. The Investigator will email the product complaint reports to 
sdriessen@effrx.com and safety@effrx.com. Should any such concerns or irregularities occur, 
the IMP will not be used until confirms that it is permissible to use was received.  
 
Examples of Product Complaints: 
• Packaging: for example, broken container or cracked container 
• Usage: for example, subject or healthcare provider cannot appropriately use the product 
• Labeling: for example, missing labels, illegible labels, incorrect labels, and/or suspect labels 
• Change in IMP appearance: for example color change or presence of foreign material 
• Unexpected quantity in bottle: for example number of tablets or amount of fluid 
• Evidence of tampering or stolen material 
 
8. Concomitant therapy 
In patients treated for osteoporosis symptomatic hypocalcemia has occurred, generally in 
association with predisposing conditions. Therefore, patients must be adequately supplemented 
with calcium and vitamin D levels during Steovess therapy. A calcium (1000 mg) and vitamin 
D (880 IU) supplement will be provided during the study visits as of the baseline visit. Daily 
intake following the approved dosage and regimen is requested. This supplement is considered 
to be an auxiliary medicinal products.  Relabeling is not requested. 
 
9. End of study 
End of study is 30 days after the last visit at week 48 of last patient.  
 
 


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10. Adverse Events/Adverse Event reporting 
The investigator will monitor each subject for clinical and laboratory (serum Ca++ levels) 
evidence of adverse events on a routine basis throughout the study.  The investigator will assess 
and record any adverse event in detail on the adverse event CRF including the date and time of 
onset, description, seriousness, severity, time course, duration and outcome, relationship of the 
adverse event to study drug, an alternate etiology for events not considered "probably related" 
to study drug, final diagnosis/syndrome (if known) and any action(s) taken. Adverse events, 
whether in response to a query, observed by study-site personnel, or reported spontaneously by 
the subject, will be recorded. 
All adverse events will be followed to a satisfactory conclusion. 
 
10.1. Definition 
Adverse Event 
An adverse event is defined as any untoward medical occurrence in a subject or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal product, whether or not the event is 
considered causally related to the use of the product. 
Such an event can result from use of the drug as stipulated in the protocol or labeling, as well 
as from accidental or intentional overdose, drug abuse, or drug withdrawal.  Any worsening of 
a pre-existing condition or illness is considered an adverse event. Laboratory abnormalities and 
changes in vital signs are considered to be adverse events only if they result in permanent or 
temporary discontinuation of treatment with effervescent alendronate, necessitate therapeutic 
medical intervention and/or if the investigator considers them to be adverse events. 
An elective surgery/procedure scheduled to occur during a study will not be considered an 
adverse event. However, if a pre-existing condition deteriorates unexpectedly during the trial 
(e.g., surgery performed earlier than planned), then the deterioration of the condition for which 
the elective surgery/procedure is being done will be considered an adverse event.  
Serious Adverse Event 
If an adverse event meets any of the following criteria, it is to be considered as serious: 
Death of Subject 
An event that results in the death of a subject. 
Life-Threatening 
An event that, in the opinion of the investigator, would 
have resulted in immediate fatality if medical intervention 
had not been taken.  This does not include an event that 


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would have been fatal if it had occurred in a more severe 
form. 
Hospitalization 
An event that results in an admission to the hospital for any 
length of time.  This does not include an emergency room 
visit or admission to an outpatient facility. 
Prolongation of 
Hospitalization 
An event that occurs while the study subject is hospitalized 
and prolongs the subject’s hospital stay. 
Congenital Anomaly 
An anomaly detected at or after birth, or any anomaly that 
results in fetal loss. 
Persistent or Significant 
Disability/Incapacity 
An event that results in a condition that substantially 
interferes with the activities of daily living of a study 
subject.  Disability is not intended to include experiences 
of relatively minor medical significance such as headache, 
nausea, vomiting, diarrhea, influenza, and accidental 
trauma (e.g., sprained ankle). 
Important Medical Event 
Requiring Medical or 
Surgical Intervention to 
Prevent Serious Outcome 
An important medical event that may not be immediately 
life-threatening or result in death or hospitalization, but 
based on medical judgment may jeopardize the subject and 
may require medical or surgical intervention to prevent any 
of the outcomes listed above (i.e., death of subject, life-
threatening, 
hospitalization, 
prolongation 
of 
hospitalization, congenital anomaly, or persistent or 
significant disability/incapacity).  Examples of such events 
include 
allergic 
bronchospasm 
requiring 
intensive 
treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or 
drug abuse. 
Spontaneous Abortion 
Miscarriage experienced by study subject. 
Elective Abortion 
Elective abortion performed on study subject. 
 
Adverse Event Severity 
The investigator will use the following definitions to define/rate the severity of each adverse 
event: 
Mild 
The adverse event is transient and easily tolerated by the subject. 
Moderate 
The adverse event causes the subject discomfort and interrupts the 
subject’s usual activities. 


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Severe 
The adverse event causes considerable interference with the subject’s 
usual activities and may be incapacitating or life-threatening. 
 
Relationship to Study Drug 
The investigator will use the following definitions to assess the relationship of the adverse event 
to the use of study drug: 
Probably Related 
An adverse event has a strong temporal relationship to study drug or 
recurs on re-challenge and another etiology is unlikely or significantly 
less likely. 
Possibly Related 
An adverse event has a strong temporal relationship to the study drug 
and an alternative etiology is equally or less likely compared to the 
potential relationship to study drug. 
Probably Not 
Related 
An adverse event has little or no temporal relationship to the study 
drug and/or a more likely alternative etiology exists. 
Not Related 
An adverse event is due to an underlying or concurrent illness or effect 
of another drug and is not related to the study drug (e.g., has no 
temporal relationship to study drug or has a much more likely 
alternative etiology). 
 
10.2. Adverse Event Reporting 
Reporting will be consistent with current safety reporting standards. Adverse events will be 
reported between the first dose administration of trial medication and the last trial related 
activity. 
All AEs and SAE’s will be recorded in the patient’s file and in the CRF. All SAE’s will be 
reported as described below.  A list of AEs considered possibly or probably related to 
Steovess/Binosto should be forwarded to EffRx at the end of the study at the latest. 
 
Medical events that occur between signing of the Informed Consent and the first intake of trial 
medication will be documented on the medical and surgical history section and concomitant 
diseases page of the CRF. 
 
SAE’s occurring within a period of 30 days following the last intake of trial medication will 
also be handled as such if spontaneously reported to the investigator. 
All serious adverse events (SAE) and pregnancies spanning from the first intake of IMP until 
the end of the study must be reported by the local Principal Investigator within 24h after 
becoming aware of the SAE to: 
- 
The local EC 
- 
Health, innovation and research institute (HIRUZ) 
- 
The designated contact person of the Marketing Authorisation Holder (MAH) or 
producer of the medicinal (investigational) product 
 


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This reporting is done by using the appropriate SAE form. For the contact details, see below. 
It is the responsibility of the local Principal Investigator to report the local SAE’s  to the local 
EC. 
In case the investigator decides the SAE is a SUSAR (Suspected Unexpected Serious Adverse 
Reaction), HIRUZ will report the SUSAR to the Central EC and the CA within the timelines as 
defined in national legislation.  
In case of a life-threatening SUSAR the entire reporting process must be completed within 7 
calendar days.  In case of a nonlife-threatening SUSAR the reporting process must  completed 
within 15 calendar days. 
The first report of a serious adverse event may be made by telephone, e-mail or facsimile 
(FAX).  
Contact details of HIRUZ: 
e-mail: hiruz.ctu@uzgent.be  
tel.: 09/332 05 00 
fax: 09/332 05 20 
Contact details of producer: Pharmacovigilance department 
e-mail: safety@effrx.com 
tel. : +41 44 503 78 60 
 
The investigator must provide the minimal information: i.e. trial number, subject's initials and 
year of birth, medication code number, period of intake, nature of the adverse event and 
investigator's attribution. 
A report of a serious adverse event by telephone must always be confirmed by a written, more 
detailed report. For this purpose the appropriate SAE form will be used. Pregnancies occurring 
during clinical trials are considered immediately reportable events. They must be reported as 
soon as possible using the same SAE form. The outcome of the pregnancy must also be 
reported. 
 
As the subjects are not under 24-hour supervision of the investigator or his/her staff, 
they must be provided with a "trial card" indicating the name of the investigational 
product, the trial number, the investigator's name and a 24-hour emergency contact 
number. 
Annual Safety and Progress Reporting 
Hiruz CTU will ask the Chief Investigator for an annual report containing information on the 
status of the trial and an overview of all SSARs (Suspected Serious Adverse Reaction) and a 
summary regarding the safety of the trial subjects. Hiruz CTU will send this report to the Central 
EC and the CA within the timelines as defined in national legislation.  
 
 


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11. Statistical and Analytical Plans 
 
11.1 
 Efficacy analysis 
Complete and specific details of the final statistical analysis will be described and fully 
documented in the Statistical Analysis Plan (SAP). The SAP will be finalized prior to the 
database lock. The analysis will be performed using the statistical software package IBM SPSS.  
Demographic and baseline characteristics will be summarized. The number of observations, 
mean, standard deviation, median, minimum and maximum will be summarized for continuous 
variables. Discrete variables will be summarized by counts and percentages.  
Primary analysis will be a per protocol approach, including all patients who completed the final 
visit (week 48). Missing data related to exploratory endpoints will be handled by last 
observation carried forward (LOCF) procedure. 
The primary efficacy variables will be the number of patients that maintain CTx-I within the 
premenopausal reference range at week 48. Secondary efficacy variables will be the changes 
from baseline to week 12, 24 and 48 for CTx-I and P1NP levels.  Co-exploratory variables will 
be DXA changes from baseline to week 24 and 48. Hand OA-related exploratory efficacy 
variables will be changes in NRS pain from baseline to week 12, 24 and 48, and changes in 
number of new erosive joints on X-rays and changes in GUSS values from baseline to W24 and 
48.  
All analyses be summarized by treatment group where treatment group equals ‘exposed to 
Alendronate for 48 weeks Vs Alendronate for 24 weeks’. 
 
11.2 
Safety analysis 
Safety analyses will be carried out using the safety population, which includes all subjects who 
received at least one dose of study drug. Treatment-emergent AEs and SAEs will be 
summarized and reported. The number and percentage of subjects experiencing adverse events 
will be provided by system organ class and Medical Dictionary for Drug Regulatory Activities 
(MedDRA) preferred term. In addition, summary of AEs by severity and relationship to study 
drug will be presented. Serious, severe AEs, or AEs that lead to premature study discontinuation 
will be listed and described in detail. Mean change in vital signs and laboratory variables at 
each visit will be summarized for all treated subjects, and compared between treatment groups 
using one way Analysis of Variance (ANOVA).  
 
11.3 
Determination of Sample size  
No formal sample size calculation has been performed: No recruitment or inclusion of patients 
that did not participated the previous phases (Randomized controlled trial and open label 
extension phase) is possible and the sample size of this study is therefore limited to a maximum, 
i.e. the number of patients ending the extension phase and being willing to participate.  
 
12. Quality assurance and periodic monitoring  
The investigator will maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents will 
be classified into two different categories: investigator's file, and subject clinical source 
documents. 


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The investigator's file will contain the documents as per Good Clinical Practice and local 
regulations. 
Regular monitoring will be performed by Hiruz CTU according to ICH-GCP. Data will be 
evaluated for compliance with the protocol and accuracy in relation to source documents. 
Following written standard operating procedures, the monitors will verify that the clinical trial 
is conducted and data are generated, documented and reported in compliance with the protocol, 
GCP and the applicable regulatory requirements. At least 3 monitoring visits are scheduled. An 
initiation visit, one routine visit and a final visit after the last patient had finished the study. The 
monitor will be working according to SOPs and will provide a monitoring report after each visit 
for the sponsor and the investigator. Depending on the quality of the data, additional monitoring 
visits will be necessary according to the sponsor’s discretion. 
More detailed information regarding the monitoring is described in the monitoring plan.  
 
13.  Indemnity insurance 
An insurance with no fault responsibility has been foreseen by the sponsor in accordance with 
the Belgian law concerning experiments on humans, 7 May 2004.. 
 
14.  Publication Policy 
The results of this study will be reported and published at conferences and in peer-reviewed 
clinical journals. Authorship publications will follow the Uniform Requirement for Manuscripts 
Submitted to Biomedical Journals (International Committee of Medical Journal Editors, 2009), 
which states: 
Authorship credit should be based on (1) substantial contributions to conception and design, 
acquisition of data, or analysis and interpretation of data; (2) drafting the article or revising it 
critically for important intellectual content; (3) final approval of the version to be published and 
(4) Agreement to be accountable for all aspects of the work in ensuring that questions related 
to the accuracy or integrity of any part of the work are appropriately investigated and resolved. 
Authors should meet conditions 1, 2, 3 and 4.  
For further details , see http://www.icmje.org/recommendations/browse/roles-and-
responsibilities/defining-the-role-of-authors-and-contributors.html. 
 
15. Final Report 
Within one year after the final completion of the study, a full final report will be written by 
the Chief Investigator and submitted to the central ethical committee and competent authority 
(via Hiruz CTU).  
 
 


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Part II : General part of the protocol 
 
16. Independent Ethics Committee (IEC) / Institutional Review Bord (IRB) 
This trial can only be undertaken after full approval of the protocol and addenda has been 
obtained from the IEC/IRB. This document must be dated and clearly identify the protocol, 
amendments (if any), the informed consent form and any applicable recruiting materials and 
subject compensation programs approved. 
During the trial, the following documents will be sent to the IEC/IRB for their review: 
 reports of adverse events that are serious, unexpected and associated with the 
investigational drug 
 all protocol amendments and revised informed consent form (if any). 
Amendments should not be implemented without prior review and documented approval / 
favorable opinion form the IEC/IRB except when necessary to eliminate an immediate hazard 
to trial subjects or when the change involves only logistical or administrative aspects of the 
trial. 
Reports on, and reviews of the trial and its progress will be submitted to the IEC/IRB by the 
investigator at intervals stipulated in their guidelines. 
At the end of the trial, the investigator will notify the IEC/IRB about the trial completion. 
 
17. Competent Authority (CA) 
This study must obtain approval from the competent authority (FAGG) prior to the start of the 
study.  All protocol amendments will be notified to the competent authorities during the course 
of the trial.  
Reports on safety, and reviews of the trial and its progress will be submitted to the CA by the 
sponsor (via Hiruz CTU) at intervals stipulated in their guidelines. 
At the end of the trial, the sponsor will notify the CA (via Hiruz CTU) about the trial completion 
as per regulatory requirements. 
 
18.  Early termination 
Early termination or suspension of the study or an investigational site may be necessary in case 
of major non-compliance, critical safety issues or premature trial discontinuation. This can 
occur at any time by the sponsor, principal investigator of the local site, EC or regulatory 
authority. In the event that the clinical investigation would be discontinued prematurely, all 
clinical investigation products will be retained, the terminating party shall justify its decision 
in writing and the sponsor will communicate (via Hiruz CTU) early termination, including the 
reason for early termination, to the EC and regulatory authority. 
 
19. Protocol compliance  
Prospective, planned deviations or waivers to the protocol are not allowed. Under emergency 
circumstances, deviations from the protocol to protect the rights, safety or well-being of human 


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subjects may proceed without prior approval of the sponsor and the EC. Such deviations shall 
be documented and reported to Hiruz CTU by email (hiruz.ctu@uzgent.be) and the EC as soon 
as possible. Accidental protocol deviations must be adequately documented and reported in the 
CRF on the protocol deviation log. In case accidental protocol deviations are considered as 
critical issues that significantly affect patient safety, data integrity and/or study conduct these 
should be reported to Hiruz CTU immediately by email (hiruz.ctu@uzgent.be). Hiruz CTU will 
subsequently communicate and discuss this with the EC. 
The following items will be documented on the protocol deviation log: date of deviation, 
description of deviation, actions taken and classification of deviation. Deviations will be 
classified as minor or major. A minor protocol deviation is a deviation that does not affect the 
safety, rights or well-being of subjects or the quality of their data. A major protocol deviation 
is a deviation that affects safety, rights or well-being of subjects or quality of their data. 
 Any deviation that potentially interferes with and/or affects the efficiency and/or quality 
conduct of the study will be discussed by the monitor with the PI and will be documented on 
the monitoring report including a proposed plan of action for resolution if applicable. 
 
20. ICH/GCP guidelines 
This trial will be conducted in accordance with the protocol, current ICH-GCP guidelines and 
applicable law(s). 
Good Clinical Practice (GCP) is an international ethical and scientific quality standard for 
designing, conducting, recording and reporting trials that involve the participation of human 
subjects. Compliance with this standard provides public assurance that the rights, safety and 
well-being of trial subjects are protected, consistent with the principles that have their origin in 
the Declaration of Helsinki, and that the clinical trial data are credible. 
 
21. Subject information and informed consent 
Prior to entry in the trial, the investigator must explain to potential subjects the trial and the 
implication of participation. Subjects will be informed that their participation is voluntary and 
that they may withdraw consent to participate at any time. Participating subjects will be told 
that their records may be accessed by competent authorities and by authorized persons without 
violating the confidentiality of the subject, to the extent permitted by the applicable law(s) 
and/or regulations. By signing the Informed Consent Form (ICF), the subjects are authorizing 
such access. 
After this explanation and before entry to the trial, written, dated and signed informed consent 
should be obtained from the subject. The ICF should be provided in a language sufficiently 
understood by the subject. Subjects must be given the opportunity to ask questions. 
The subject will be given sufficient time to read the ICF and to ask additional questions. After 
this explanation and before entry to the trial, consent should be appropriately recorded by means 
of the subject's dated signature or the signature of an independent witness who certifies the 
subject's consent in writing. After having obtained the consent, a copy of the ICF must be given 
to the subject. 
In case the subject is unable to read, an impartial witness must attest the informed consent. 
 


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22. Case Report Forms 
The source documents are to be completed at the time of the subject’s visit. The CRFs are to be 
completed within reasonable time after the subject’s visit. 
The investigator must verify that all data entries in the CRFs are accurate and correct. If certain 
information is Not Done, Not Available or Not Applicable, the investigator must enter "N.D." 
or "N.AV." or "N.AP", respectively in the appropriate space. 
 
23. Direct access to source data / documents 
The investigator will permit trial-related monitoring, audits, IRB/IEC review, and regulatory 
inspection(s), providing direct access to source data/documents. 
 
24. Data handling and record keeping 
The investigator and sponsor specific essential documents will be retained for at least 20 years. 
At that moment, it will be judged whether it is necessary to retain them for a longer period, 
according to applicable regulatory or other requirement(s). 
 
 


The use of Steovess/Binosto after denosumab discontinuation to prevent increase in bone turnover. 
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Protocol version 1.0 - 09 AUG 2019  
 
25. References 
 
1. Miller PD, Bolognese MA, Lewiecki EM, et al. Effect of denosumab on bone density and turnover in 
postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: 
a randomized blinded phase 2 clinical trial. Bone. 2008;43:222-229. 
2. Brown JP, Roux C, Törring O, et al. Discontinuation of denosumab and associated fracture incidence: analysis 
from the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) Trial. J Bone 
Miner Res. 2013;28:746-752. 
3. Cummings SR, Ferrari S, Eastell R, et al. Vertebral fractures after discontinuation of denosumab: a post hoc 
analysis of the randomized placebo-controlled FREEDOM trial and its extension. J Bone Miner Res. 2018;33:190-
198. 
4. Freemantle N, Satram-Hoang S, Tang ET, et al. Final results of the DAPS (Denosumab Adherence Preference 
Satisfaction) study: a 24-month, randomized, crossover comparison with alendronate in postmenopausal 
women. Osteoporos Int. 2012;23:317-326. 
5. Cohen SB, Dore RK, Lane NE, Ory PA, Peterfy CG, Sharp JT, van der Heijde D, Zhou L, Tsuji W, Newmark R; 
Denosumab Rheumatoid Arthritis Study Group. Denosumab treatment effects on structural damage, bone 
mineral density, and bone turnover in rheumatoid arthritis: a twelve-month, multicenter, randomized, double-
blind, placebo-controlled, phase II clinical trial. Arthritis Rheum. 2008;58:1299-309. 
6. Ishiguro N, Tanaka Y, Yamanaka H, Yoneda T, Ohira T, Okubo N, Genant HK, van der Heijde D and Takeuchi T. 
Consistent Inhibition of Bone Destruction By Denosumab in Important Subgroups of Japanese Patients with 
Rheumatoid Arthritis. Arthritis Rheumatol 2014; 66:11(Suppl): S831/Presented at ACR meeting 2014 
7. Prolia SmPC. Sections 4.4 & 4.838.  
8. Bone HG, Chapurlat R, Brandi ML, Brown JP, Czerwinski E, Krieg MA, Mellström D, Radominski SC, Reginster 
JY, Resch H, Ivorra JA, Roux C, Vittinghoff E, Daizadeh NS, , Bradley MN, Franchimont N, Geller ML, Wagman RB, 
Cummings SR, Papapoulos S. The effect of three or six years of denosumab exposure in women with 
postmenopausal osteoporosis: results from the FREEDOM extension. Clin Endocrinol Metab. 2013;98:        4483-
92. 
9. Papapoulos S, et al. Eight Years of Denosumab Treatment in Postmenopausal Women with Osteoporosis: 
Results From the First Five Years of the FREEDOM extension. WCO-IOF-ESCEO Congress 2014. Osteoporis Int 
2014; 25 (Suppl 2):S118 
10. Rogers MJ. New insights into the molecular mechanisms of action of bisphosphonates. Curr Pharm Des 
2003;9:2643–58. 
 
11. van Staa TP, Leufkens HG, Cooper C. The epidemiology of corticosteroid-induced osteoporosis: a meta-
analysis. Osteoporos Int 2002;13:777–87. 
 
12. Adachi JD, Saag KG, Delmas PD, et al. Two-year effects of alendronate on bone mineral density and 
vertebral fracture in patients receiving glucocorticoids: a randomized, double-blind, placebo-controlled 
extension trial. Arthritis Rheum 2001;44:202–11. 
 
13. Black DM FIT Lancet 1996_348_1535-41  
 
14. Cummings SR Effect of ALN in women without vertebral Fx JAMA 1998  
 
15. Black DM FIT Combined Study Group J Clin Endocrinol Metab 2000_85_4118-4124 
 


The use of Steovess/Binosto after denosumab discontinuation to prevent increase in bone turnover. 
August 09 2019 – Version 1.0 
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Protocol version 1.0 - 09 AUG 2019  
16. Lin JT, Lane JM. Bisphosphonates. J Am Acad Orthop Surg 2003;11:1–4. 
 
17. Madore GR, Sherman PJ, Lane JM. Parathyroid hormone. J Am Acad Orthop Surg 2004;12:67–71. 
 
18. Plotkin LI, Weinstein RS, Parfitt AM, et al. Prevention of osteocyte and osteoblast apoptosis by 
bisphosphonates and calcitonin. J Clin Invest 1999;104:1363–74. 
 
19. Giuliani N, Pedrazzoni M, Negri G, et al. Bisphosphonates stimulate formation of osteoblast precursors and 
mineralized nodules in murine and human bone marrow cultures in vitro and promote early osteoblastogenesis 
in young and aged mice in vivo. Bone 1998; 
22:455–61. 
 
20. Ya-Kang Wang, Yu-min Zhang, Si-Qing Qin, Xu Wang, Tao Ma, Jian-Bin Guo, Chao Zhu, Zhuo-Jing Luo, Effects 
of alendronate for treatment of glucocorticoid-induced osteoporosis: A meta-analysis of randomized controlled 
trials. Medicine (2018) 97:42 
 
21. Steovess/Binosto  SmPC. Section 5 
22. Hodges LA et al. Modulation of gastric pH by a buffered soluble effervescent formulation: A possible means 
of improving gastric tolerability of alendronate.  Int J Pharm 2012; 432 :57-62 
 
 
 
 


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Annex I 
IMP label 
 
EudraCT N°: 2019-003570-11 
TRIAL subject ID nr°: ______ Initialen: _____ Datum visite: ____ 
ENKEL VOOR STUDIEGEBRUIK 
Gebruiksaanwijzing: eenmaal per week een in leidingwater opgeloste bruistablet – 12  bruistabletten 
Elke bruistablet bevat 70mg alendronaat – Voor oraal gebruik – Buiten het zicht en bereik van 
kinderen houden – Bewaar in de originele verpakking ter bescherming tegen vocht. 
UNIQUEMENT POUR UTILISATION DE L’ESSAI CLINIQUE 
Mode d’emploi : un comprimé effervescent une fois par semaine, sous forme de solution buvable – 12 
comprimés effervescents – Chaque comprimé contient d’alendronate 70mg – Voie orale – Tenir hors 
de la vue et de la portée des enfants - A conserver dans l’emballage extérieur d’origine, à l’abri de 
l’humidité. 
NUR STUDIENGEBRAUCH KLINISCHER  
Gebrauchsanweizung: Nehmen Sie einmal pro Woche eine in Leitungswasser gelöste Brausetablette 
ein. – 12 Brausetabletten - Jede Brausetablette enthält 70mg Alendronat - oraler Einnahme - 
Artznemittel für Kinder unzugänglich aufbewahren - In der Originalverpackung aufbewahren, um den 
Inhalt vor Feuchtigkeit zu schützen  
Exp : dayMONTHyear 
PROF. WITTOEK R.  TEL: 09/332 25 22 – 09/332 21 11 
SPONSOR: UZ GENT C. Heymanslaan 10 9000 GENT 

SAP_001.pdf: 
1 
 
Statistical analysis plan 
 
The Use of Steovess/Binosto After Denosumab Discontinuation to Prevent 
Increase in Bone Turnover 
 
NCT04403698 
EudraCT number: 2019-003570-11 
Protocolnumber: BC-6072 
 
 
Principal investigator:  
Ruth Wittoek, MD, PhD, Dept. of Rheumatology- Ghent University Hospital  
Subinvestigators: 
Dirk Elewaut, MD, PhD, Dept. of Rheumatology- Ghent University Hospital 
Tine Vanhaverbeke, MD, Dept. of Rheumatology- Ghent University Hospital 
 
 
Author: Tine Vanhaverbeke 
Date: 04/12/2024 
Version 2 
 
 


2 
 
Content 
1. Study identification ................................................................................................................ 3 
1.1 Study details ........................................................................................................................ 3 
1.2 SAP details........................................................................................................................... 3 
2. Background and rationale of the study........................................................................................ 4 
2.1 Background ......................................................................................................................... 4 
2.2 Hypothesis and objectives .................................................................................................... 4 
2.3 Study design ........................................................................................................................ 4 
3. Study population ....................................................................................................................... 5 
3.1 Inclusion and exclusion criteria ............................................................................................. 5 
3.1.1. Inclusion criteria ........................................................................................................... 5 
3.1.2 Exclusion criteria ........................................................................................................... 5 
3.2 Data sets analysed ............................................................................................................... 5 
3.2.1 Safety analysis ............................................................................................................... 5 
3.2.2 Full analysis dataset ....................................................................................................... 5 
3.2.3 Protocol violations and handling of missing data.............................................................. 5 
4. Outcome measures.................................................................................................................... 6 
4.1 Primary endpoints ............................................................................................................... 6 
4.2 Secondary endpoints............................................................................................................ 6 
4.3 Safety data .......................................................................................................................... 6 
4.3 Exploratory outcomes measures ........................................................................................... 6 
5. Statistical analysis ...................................................................................................................... 6 
5.1 Summary of baseline data .................................................................................................... 7 
5.2 Primary outcome analysis..................................................................................................... 7 
5.3 Secondary outcome analysis ................................................................................................. 7 
5.4 Exploratory outcome measure analysis.................................................................................. 7 
6. Timeline.................................................................................................................................... 7 
7. References ................................................................................................................................ 8 
 
 
 


3 
 
1. Study identification 
1.1 Study details 
Title: The use of buffered soluble alendronate 70 mg (Steovess/Binosto) after denosumab  
discontinuation to prevent increase in bone turnover 
Trial registration number: EudraCTNr: 2019-003570-11 
EC approval number: BC-6072 
Principal investigators: Ruth Wittoek  
Subinvestigators: Dirk Elewaut, Tine Vanhaverbeke  
Study type: Investigator Sponsored Study  
Funder: Amgen and EffRx Pharmaceuticals  
 
Protocol: version 1.0 dd 09/08/2019 
1.2 SAP details 
SAP Author: Tine Vanhaverbeke  
Statistician: Roos Colman 
 
 
 
 


4 
 
2. Background and rationale of the study  
2.1 Background  
Denosumab, anti-RANK ligand therapy discontinuation, is associated with a rebound in bone turnover 
and loss of bone mineral density. These changes result in increased fracture incidence in patients with 
postmenopausal osteoporosis back to background levels. Amongst the patients that presented with 
vertebral fractures after treatment discontinuation, there is a slightly higher incidence of multiple 
vertebral fractures in patients discontinuing Prolia versus those that discontinued placebo. 
In our study ‘RANKL-blockade for the treatment of erosive hand osteoarthritis (OA) of interphalangeal 
finger joints’ (EudraCT number: 2015-003223-53; Protocolnumber: AGO/2015/008) patients are 
randomized to placebo or denosumab (60 mg/Q3M) for 1 year followed by a two-year open label 
extension in which all subjects receive denosumab (60 mg/Q3M) (1). Also in this non-osteoporotic 
population, increases in bone turnover are expected as soon as patients end study participation. 
It is currently recommended that other anti-resorptive therapy may is warranted after Denosumab 
discontinuation. Several studies describe the use of oral alendronate after denosumab therapy to 
maintain bone mineral density. However, gastro-intestinal upset and tolerability, as well as difficulty 
swallowing pills may limit oral alendronate use. In the current study proposal we want to examine the 
use of effervescent alendronate (Steovess/Binosto) in subjects that completed our hand erosive 
osteoarthritis study and therefore discontinued denosumab 60 mg/Q3M.We hypothesize that 
Steovess/Binosto will be able to maintain bone turnover markers within the reference range thereby 
reducing the likelihood of bone turnover associated changes. 
In erosive hand OA, destructive erosive changes, followed by remodelling is key characteristic for the 
disease. As in inflammatory rheumatic diseases, the RANKL pathway appears to be involved in the 
pathogenesis and hence, a therapeutic role of its blockade has been studied in the study described 
above. It is unknown if a potential rebound effect in bone turnover might also be associated with a 
rebound in erosive destructive progression at the subchondral bone. 
2.2 Hypothesis and objectives  
It is hypothesized that effervescent alendronate will be able to maintain bone turnover markers 
within the reference range thereby reducing the likelihood of bone turnover associated changes, after 
discontinuation of denosumab treatment in a non-osteoporotic population. 
The primary objective of this study is to assess the effect of effervescent alendronate after 
denosumab discontinuation on the change in bone turnover markers after 48 weeks in a non-
osteoporotic population and to assess if there is a difference between using oral alendronate after 24 
or 48 weeks.  
The secondary objective is to evaluate the effect of effervescent alendronate after denosumab 
discontinuation on bone mineral density in this non-osteoporotic population and assess difference in 
oral alendronate therapy for 24 versus 48 weeks.   
Exploratory objectives are to study the effect of oral alendronate therapy after denosumab 
discontinuation on erosive destructive progression at the subchondral bone in erosive hand OA 
patients and to assess the effect of oral alendronate on their hand pain scores.  
2.3 Study design  
This is a monocentric randomized study to investigate the effect of effervescent alendronate on bone 
turnover markers after denosumab discontinuation. At the earliest three months but no later than 


5 
 
four months after the last denosumab injection, 40 subjects will be randomized to effervescent 
alendronate administered for either 24 (n=20) or 48 weeks (n=20). The randomization was performed 
by a randomization manager. The total treatment duration per subject is 48 weeks.  
3. Study population  
3.1 Inclusion and exclusion criteria  
Cfr Protocol (version 1.0 dd 09/08/2019) 
3.1.1. Inclusion criteria  
A subject will be eligible for study participation if he/she meets the following criteria: 
• 
Subjects must have completed the 48 weeks of the randomised placebo-controlled study 
phase followed by the 96 weeks open label denosumab 60 mg SC every 3 months phase. 
(EudraCT number: 2015-003223-53) 
• 
Last denosumab injection less than four months ago 
• 
Able and willing to give written informed consent and to comply with the requirements of the 
study protocol 
3.1.2 Exclusion criteria  
A subject will be excluded from the study if he/she meets any of the following criteria:  
• 
Patients with clinically significant hypersensitivity to any of the components of effervescent 
alendronate.  
• 
Patient who is pregnant or planning pregnancy  
• 
Female subjects who are breast-feeding.  
• 
History of osteonecrosis of the jaw, and/or recent (within 3 months) tooth extraction or other 
unhealed dental surgery; or planned invasive dental work during the study  
• 
Subject has any kind of disorder that compromises the ability of the subject to give written 
informed consent and/or to comply with study procedures  
• 
Hypocalcaemia.  
• 
Oesophageal disease, gastritis, duodenitis, ulcers, or with a recent history (within the 
previous year) of major gastro-intestinal disease such as peptic ulcer, or active gastro-
intestinal bleeding, or surgery of the upper gastro-intestinal tract other than pyloroplasty.  
• 
Abnormalities of the oesophagus and other factors which delay oesophageal emptying such 
as stricture or achalasia.  
• 
Inability to stand or sit upright for at least 30 minutes.  
 
3.2 Data sets analysed  
3.2.1 Safety analysis  
The safety dataset includes all patients who received at least 1 dose of effervescent alendronate. This 
dataset will be used to summarize adverse events and safety analysis.  
 
3.2.2 Full analysis dataset  
The full analysis set will include all patients who are randomly allocated to a treatment group and 
received at least 1 dose of effervescent alendronate. 
 
3.2.3 Protocol violations and handling of missing data  
Major protocol violations thought to affect the assessment of efficacy of the study drug will be 
considered. The following situations will be considered as major protocol violations:  


6 
 
• 
Patients who withdrew or were withdrawn from the study  
• 
Patients  having received less than 50% of the study medication  
 
Data of withdrawn patients will be included up until the moment of withdrawal. If measurements are 
recorded after withdrawal when not completed the appropriate duration of active treatment, these 
measurements will be considered as missing. For analysis of the primary endpoint, all data available 
will be used for analysis and imputation of missing values will be performed. More specifically, drop-
outs will be considered as non-responders in all outcome measures (primary and secondary 
endpoints where linear mixed models will be used, and in the number of patients exceeding 
reference ranges). Only in the analyses of percentage changes of BMD and percentage of patients 
with a BMD loss higher than the least significant change, drop-outs will be considered as true drop-
outs.   
 
 
4. Outcome measures  
4.1 Primary endpoints 
The primary end point of this study is to investigate if effervescent alendronate is able to maintain 
bone turnover markers after discontinuation of denosumab in a non-osteoporotic population. The 
outcome measures being used for this are the bone turnover markers CTX-I (C-terminal telopeptide 
of type I collagen) a marker that reflects the breakdown of bone and PINP (N-terminal propeptide of 
type I collagen) a marker that reflects the formation of new bone.  The primary end point will be the 
difference in these bone turnover markers after 48 weeks between both treatment arms.  
4.2 Secondary endpoints 
Secondary end points are changes in bone mineral density (BMD) at the femoral neck and spine at 
week 48, the number of patients from both groups maintaining CTX-I and PINP levels within reference 
range values at week 12, 24 and 48. Reference ranges used will be adjusted according to menopausal 
status and sex. Percentage changes in BMD and the percentage of patients with a BMD loss higher 
than the least significant change (LSC), which represents the smallest difference between successive 
measurements of BMD that can be considered a real change, will be calculated. 
4.3 Safety data  
Analysis of the safety data set will be performed. This will include the occurrence on incidence and 
severity of adverse events and serious adverse events. These will be categorized according to the 
involved organ systems. The number of the events will be reported and compared between both 
treatment groups.  Changes in routine clinical laboratory tests (calcium, vitamin D, creatinine, urine 
and GFR) will also be analyses  
 
4.3 Exploratory outcomes measures  
Exploratory end points are the development of new erosive joints (using the Verbruggen and Veys 
anatomical phase scoring system) (2) and hand pain scores, measured using a NRS pain scale at week 
48.  
5. Statistical analysis  
All statistical analyses will be performed using R and RStudio (version 4.1.1).  


7 
 
All continuous variable will summarized using mean and standard deviation (SD). Frequency count 
and percentages will be used to summarise categorical variables.  
5.1 Summary of baseline data  
A brief summary of descriptive statistics will be provided including demographic features and disease 
specific characteristics.  Demographic baseline data will be compared between both treatment 
groups.  
5.2 Primary outcome analysis  
The primary outcome analysis will be performed in an intention to treat approach, where drop-outs 
were considered as non-responders. Changes in bone turnover marker levels will be analysed with a 
linear mixed model. Data from all available time points will be used. Normal distribution will be 
checked and data transformations will be performed if necessary if assumptions of normality aren’t 
reached. P-values and estimated marginal means will be calculated at different time points.  
All analyses will be performed with a two-sided p-value. A p-value below 0.05 (p<0.05) will be 
considered statistically significant. 
5.3 Secondary outcome analysis  
Bone density measures will be analysed in an intention to treat approach, using a linear mixed model. 
Data from all available time points will be used. Normal distribution will be checked and data 
transformations will be performed if necessary if assumptions of normality are not reached. P-values 
and estimated marginal means will be calculated at different time points.  
In addition, percentage changes in BMD and the percentage of patients with a BMD loss higher than 
the least significant change (LSC), which represents the smallest difference between successive 
measurements of BMD that can be considered a real change, will calculated. Here no intention to 
treat approach will be used.  
The number of patients exceeding reference ranges will be calculated with an intention to treat 
approach, where drop-outs will be considered as non-responders.  A Fisher’s exact test was used to 
assess differences in patient numbers exceeding reference ranges between both treatment groups. 
All statistical tests were two-tailed and a p-value below 0.05 (α) was considered statistically 
significant. 
5.4 Exploratory outcome measure analysis  
Hand pain scores will be analysed using an intention to treat approach, using a linear mixed model. 
Data from all available time points will be used. Normal distribution will be checked and data 
transformations will be performed if necessary if assumptions of normality are not reached. P-values 
and estimated marginal means will be calculated at different time points. Changes in new erosive 
joint count on radiographs, scored using the Verbruggen and Veys anatomical phase scoring system 
(2) and hand pain scores, measured using a NRS pain scale at week 48. The number and percentage 
of joints in each radiographical phase (N, S, J, E and R phase) will be reported.  The total number and 
percentage of pre-erosive joints (N,S and J phase) progressing to an erosive phase during the trial will 
also be reported.  
 
6. Timeline  
The SAP will be finalized prior to the database lock. The last visit of the last patient was foreseen in 
March 2022. Data lock will be done after June 2022. Statistical analyses will be performed from June 
2022 till approx. end of January 2023. Report to be expected Beginning of March 2023. 


8 
 
7. References  
1. 
Wittoek R VG, Vanhaverbeke T, Colman R, Elewaut D. . RANKL-blockade for erosive hand 
osteoarthritis: A randomized, placebo-controlled phase 2a trial. . Nature Medicine (accepted for 
publication). 2024. 
2. 
Verbruggen G, Veys EM. Numerical scoring systems for the anatomic evolution of 
osteoarthritis of the finger joints. Arthritis Rheum. 1996;39(2):308-20.