DEPO-SUBQ PROVERA 104® Clinical Studies

(medroxyprogesterone acetate)

14 CLINICAL STUDIES

14.1 Contraception Studies

In three open label clinical studies, depo-SubQ provera 104 (104 mg given every three months subcutaneously), was administered to healthy, sexually-active, nonpregnant women 18 to 49 years of age who desired long-term contraception. In these three studies, no pregnancies were detected among 2042 women treated with depo-subQ provera 104 for up to 1 year. In women less than 36 years of age (at baseline), the Pearl Index pregnancy rate in cycles in which no other contraceptive methods were used, was 0 pregnancies per 100 women-years of use (upper 95% CI = 0.25).

14.2 Endometriosis Studies

The efficacy of depo-subQ provera 104 in the reduction of endometriosis-associated pain in women with the signs and symptoms of endometriosis was demonstrated in two active comparator-controlled studies in pre-menopausal women 18 to 49 years of age with laparoscopically diagnosed endometriosis and persistent endometriosis pain symptoms (i.e., Studies 268 and 270). Each study assessed endometriosis-associated pain over 6 months of treatment and recurrence of symptoms for 12-months post treatment.

Subjects were treated for six months with depo-subQ provera 104 [104 mg given subcutaneously every 3 months (2 injections)] or leuprolide [11.25 mg given subcutaneously every 3 months (2 injections) or 3.75 mg given subcutaneously every month (6 injections)]. Study 268 was conducted in the U.S. and Canada and enrolled 274 subjects (136 subjects received depo-subQ provera 104 and 138 subjects received leuprolide). Study 270 was conducted in South America, Europe, and Asia, and enrolled 299 subjects (153 subjects received depo-subQ provera 104 and 146 subjects received leuprolide).

Reduction in endometriosis pain was evaluated using a modified Biberoglu and Behrman scale that consisted of three patient-reported symptoms (i.e., dysmenorrhea, dyspareunia, and pelvic pain not related to menses) and two signs assessed during pelvic examination (i.e., pelvic tenderness and induration). For each category, a favorable response was defined as improvement of at least 1 unit (severity was assessed on a scale of 0 to 3) relative to baseline score (Figure Q).

Figure Q. Responders at End of Treatment (Month 6 or Last Assessment if Earlier) in Patients with Endometriosis in Studies 268 and 270
Favorable Response = reduction in severity of symptom or sign of ≥1 point on a scale of 0 to 3, as compared to baseline.
Figure Q

Additionally, scores from each of the five categories were combined into a composite score that was considered a global measurement of overall disease improvement. For subjects with baseline scores for each of the 5 categories, a mean decrease of 4 points relative to baseline was considered a clinically meaningful improvement. Across both studies, the mean changes in the composite score met the protocol-defined criterion for improvement for the depo-subQ provera 104 and leuprolide treatment groups.

In the clinical trials, treatment with depo-subQ provera 104 was limited to six months. Data on the persistence of benefit with longer treatment are not available.

14.3 Bone Mineral Density in Women Treated with Depo-medroxyprogesterone acetate for Contraception

In a study that compared changes in bone mineral density (BMD) in adult women using depo-subQ provera 104 or DMPA-IM for contraception, both treatments showed BMD reductions in the lumbar spine, total hip, and femoral neck. Mean percent changes in BMD in depo-subQ provera 104-treated women are shown in Table 3.

Table 3. BMD Mean Percent Change from Baseline in Women Using depo-subQ provera 104 for Contraception
Time on TreatmentLumbar SpineTotal HipFemoral Neck
Mean % Change
(95% CI)		Mean % Change
(95% CI)		Mean % Change
(95% CI)

1 year
(n=166)

-2.7
(-3.1 to -2.3)

-1.7
(-2.1 to -1.3)

-1.9
(-2.5 to -1.4)

2 years
(n=106)

- 4.1
(-4.6 to -3.5)

-3.5
(-4.2 to -2.7)

-3.5
(-4.3 to -2.6)

BMD Recovery Post-Treatment in Women

Given the similar effects on BMD from depo-subQ provera 104 and DMPA-IM described above, BMD recovery post-treatment is also expected to be similar. In a controlled clinical study that compared changes in BMD in adult women using DMPA-IM for contraception or no hormonal contraception, the 2-year post-treatment follow-up demonstrated incomplete recovery of BMD following the last injection of DMPA-IM. Table 4 shows the change in BMD in women after 5 years of treatment with DMPA-IM and in the control group, as well as the extent of BMD recovery in the subset of women for whom 2-year post-treatment data were available.

Table 4. BMD Mean Percent Change from Baseline in Women by Skeletal Site and Cohort (5 Years of Treatment and 2 Years of Follow-Up)
Time in StudySpineTotal HipFemoral Neck
DMPA-IM*Control†DMPA-IM*Control†DMPA-IM*Control†
*
Women who received DMPA-IM for 5 years and were then followed for 2 years post-treatment (total time in study of 7 years).
†
Women who did not use hormonal contraception and were followed for 7 years.

5 years

-5.38%
n=33

0.43%
n=105

-5.16%
n=21

0.19%
n=65

-6.12%
n=34

-0.27%
n=106

7 years

-3.13%
n=12

0.53%
n=60

-1.34%
n=7

0.94%
n=39

-5.38%
n=13

-0.11%
n=63

14.4 Bone Mineral Density Changes in Adolescent Females (12 to 18 years of age) Treated with DMPA-IM

The effect of DMPA-IM on BMD in adolescents is described below, and the effect of depo-subQ provera 104 on BMD in adolescents is expected to be similar. The impact of DMPA-IM use for up to 240 weeks (4.6 years) was evaluated in an open-label non-randomized clinical study in 389 adolescent females (12 to 18 years of age). Use of DMPA-IM was associated with a significant decline from baseline in BMD.

Partway through the trial, DMPA-IM administration was stopped (at 120 weeks). The mean number of injections per DMPA-IM user was 9.3. Table 5 summarizes the study findings. The decline in BMD at total hip and femoral neck was greater with longer duration of use. The mean decrease in BMD at 240 weeks was more pronounced at total hip (-6.4%) and femoral neck (-5.4%) compared to lumbar spine (-2.1%).

Adolescents in the untreated cohort had an increase in BMD during the period of growth following menarche. However, the two cohorts were not matched at baseline for age, gynecologic age, race, BMD, and other factors that influence the rate of acquisition of BMD.

Table 5. BMD Mean Percent Change from Baseline in Adolescents Receiving ≥4 Injections per 60-week Period, by Skeletal Site and Cohort
Duration of TreatmentDMPA-IM (150 mg)Unmatched, Untreated Cohort
NMean % ChangeNMean % Change

Total Hip BMD

Week 60 (1.2 years)

113

-2.75

166

1.22

Week 120 (2.3 years)

73

-5.40

109

2.19

Week 240 (4.6 years)

28

-6.40

84

1.71

Femoral Neck BMD

Week 60

113

-2.96

166

1.75

Week 120

73

-5.30

108

2.83

Week 240

28

-5.40

84

1.94

Lumbar Spine BMD

Week 60

114

-2.47

167

3.39

Week 120

73

-2.74

109

5.28

Week 240

27

-2.11

84

6.40

BMD Recovery Post-Treatment in Adolescents

Longer duration of treatment and smoking were associated with less recovery of BMD following the last injection of DMPA-IM. Table 6 shows the extent of recovery of BMD up to 60 months post-treatment for adolescents who received DMPA-IM for two years or less compared to more than two years. Post-treatment follow-up showed that, in adolescents treated for more than two years, only lumbar spine BMD recovered to baseline levels after treatment was discontinued. Adolescents treated with DMPA-IM for more than two years did not recover to their baseline BMD level at the femoral neck and total hip even up to 60 months post-treatment. Adolescents in the untreated cohort gained BMD throughout the trial period [see Warnings and Precautions (5.1)].

Table 6. BMD Recovery (Months Post-Treatment) in Adolescents by Years of DMPA-IM Use (2 Years or Less vs. More than 2 Years)
Duration of Treatment
(Months)		2 Years or LessMore than 2 Years
NMean % Change from baselineNMean % Change from baseline

Total Hip BMD

End of Treatment

49

-1.5%

49

-6.2%

12 M post-treatment

33

-1.4%

24

-4.6%

24 M post-treatment

18

0.3%

17

-3.6%

36 M post-treatment

12

2.1%

11

-4.6%

48 M post-treatment

10

1.3%

9

-2.5%

60 M post-treatment

3

0.2%

2

-1.0%

Femoral Neck BMD

End of Treatment

49

-1.6%

49

-5.8%

12 M post-treatment

33

-1.4%

24

-4.3%

24 M post-treatment

18

0.5%

17

-3.8%

36 M post-treatment

12

1.2%

11

-3.8%

48 M post-treatment

10

2.0%

9

-1.7%

60 M post-treatment

3

1.0%

2

-1.9%

Lumbar Spine BMD

End of Treatment

49

-0.9%

49

-3.5%

12 M post-treatment

33

0.4%

23

-1.1%

24 M post-treatment

18

2.6%

17

1.9%

36 M post-treatment

12

2.4%

11

0.6%

48 M post-treatment

10

6.5%

9

3.5%

60 M post-treatment

3

6.2%

2

5.7%

14.5 Bone Fracture Incidence in Women Treated with Depo-medroxyprogesterone acetate for Contraception

A retrospective cohort study to assess the association between DMPA-IM injection and the incidence of bone fractures was conducted in 312,395 female contraceptive users in the UK. The incidence rates of fracture were compared between DMPA-IM users and contraceptive users who had no recorded use of DMPA-IM. The Incident Rate Ratio (IRR) for any fracture during the follow-up period (mean=5.5 years) was 1.41 (95% CI 1.35, 1.47). It is not known if this is due to DMPA-IM use or to other related lifestyle factors that have a bearing on fracture rate.

In the study, when cumulative exposure to DMPA-IM was calculated, the fracture rate in users who received fewer than 8 injections was higher than that in women who received 8 or more injections. However, it is not clear that cumulative exposure, which may include periods of intermittent use separated by periods of non-use, is a useful measure of risk, as compared to exposure measures based on continuous use.

There were very few osteoporotic fractures (fracture sites known to be related to low BMD) in the study overall, and the incidence of osteoporotic fractures was not found to be higher in DMPA-IM users compared to non-users.

Importantly, this study could not determine whether use of DMPA-IM has an effect on fracture rate later in life. Given the similar effects on BMD from depo-subQ provera 104 and DMPA-IM described above, bone fracture incidence may also be expected to be similar.

14.6 Bone Mineral Density in Women Treated with depo-SubQ provera 104 for Endometriosis

In two clinical studies of 573 adult women with endometriosis, the BMD effects of 6 months of depo-subQ provera 104 treatment (104 mg subcutaneously every 3 months) were compared to 6 months of leuprolide treatment (either 11.25 mg given subcutaneously every 3 months or 3.75 mg given subcutaneously every month). Subjects were then observed after treatment completion, for an additional 12 months. see Table 7 for the results.

Table 7. BMD Mean Percent Change from Baseline after Therapy for Endometriosis with depo-subQ provera 104 or Leuprolide for 6 Months, and 6- and 12-Months Post-Therapy (Studies 268 and 270 Combined)
Time of BMD MeasurementLumbar SpineTotal Hip
depo-subQ provera 104Leuprolidedepo-subQ provera 104Leuprolide
NMean % ChangeNMean % ChangeNMean % ChangeNMean % Change

Month 6 of treatment (End of Treatment)

208

-1.20

229

-4.10

207

-0.03

227

-1.83

6 months post-treatment

168

-1.06

180

-2.75

169

-0.05

181

-1.59

12 months post-treatment

124

-0.54

133

-1.48

125

0.39

134

-1.15

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Clinical Studies

14 CLINICAL STUDIES

14.1 Contraception Studies

In three open label clinical studies, depo-SubQ provera 104 (104 mg given every three months subcutaneously), was administered to healthy, sexually-active, nonpregnant women 18 to 49 years of age who desired long-term contraception. In these three studies, no pregnancies were detected among 2042 women treated with depo-subQ provera 104 for up to 1 year. In women less than 36 years of age (at baseline), the Pearl Index pregnancy rate in cycles in which no other contraceptive methods were used, was 0 pregnancies per 100 women-years of use (upper 95% CI = 0.25).

14.2 Endometriosis Studies

The efficacy of depo-subQ provera 104 in the reduction of endometriosis-associated pain in women with the signs and symptoms of endometriosis was demonstrated in two active comparator-controlled studies in pre-menopausal women 18 to 49 years of age with laparoscopically diagnosed endometriosis and persistent endometriosis pain symptoms (i.e., Studies 268 and 270). Each study assessed endometriosis-associated pain over 6 months of treatment and recurrence of symptoms for 12-months post treatment.

Subjects were treated for six months with depo-subQ provera 104 [104 mg given subcutaneously every 3 months (2 injections)] or leuprolide [11.25 mg given subcutaneously every 3 months (2 injections) or 3.75 mg given subcutaneously every month (6 injections)]. Study 268 was conducted in the U.S. and Canada and enrolled 274 subjects (136 subjects received depo-subQ provera 104 and 138 subjects received leuprolide). Study 270 was conducted in South America, Europe, and Asia, and enrolled 299 subjects (153 subjects received depo-subQ provera 104 and 146 subjects received leuprolide).

Reduction in endometriosis pain was evaluated using a modified Biberoglu and Behrman scale that consisted of three patient-reported symptoms (i.e., dysmenorrhea, dyspareunia, and pelvic pain not related to menses) and two signs assessed during pelvic examination (i.e., pelvic tenderness and induration). For each category, a favorable response was defined as improvement of at least 1 unit (severity was assessed on a scale of 0 to 3) relative to baseline score (Figure Q).

Figure Q. Responders at End of Treatment (Month 6 or Last Assessment if Earlier) in Patients with Endometriosis in Studies 268 and 270
Favorable Response = reduction in severity of symptom or sign of ≥1 point on a scale of 0 to 3, as compared to baseline.
Figure Q

Additionally, scores from each of the five categories were combined into a composite score that was considered a global measurement of overall disease improvement. For subjects with baseline scores for each of the 5 categories, a mean decrease of 4 points relative to baseline was considered a clinically meaningful improvement. Across both studies, the mean changes in the composite score met the protocol-defined criterion for improvement for the depo-subQ provera 104 and leuprolide treatment groups.

In the clinical trials, treatment with depo-subQ provera 104 was limited to six months. Data on the persistence of benefit with longer treatment are not available.

14.3 Bone Mineral Density in Women Treated with Depo-medroxyprogesterone acetate for Contraception

In a study that compared changes in bone mineral density (BMD) in adult women using depo-subQ provera 104 or DMPA-IM for contraception, both treatments showed BMD reductions in the lumbar spine, total hip, and femoral neck. Mean percent changes in BMD in depo-subQ provera 104-treated women are shown in Table 3.

Table 3. BMD Mean Percent Change from Baseline in Women Using depo-subQ provera 104 for Contraception
Time on TreatmentLumbar SpineTotal HipFemoral Neck
Mean % Change
(95% CI)		Mean % Change
(95% CI)		Mean % Change
(95% CI)

1 year
(n=166)

-2.7
(-3.1 to -2.3)

-1.7
(-2.1 to -1.3)

-1.9
(-2.5 to -1.4)

2 years
(n=106)

- 4.1
(-4.6 to -3.5)

-3.5
(-4.2 to -2.7)

-3.5
(-4.3 to -2.6)

BMD Recovery Post-Treatment in Women

Given the similar effects on BMD from depo-subQ provera 104 and DMPA-IM described above, BMD recovery post-treatment is also expected to be similar. In a controlled clinical study that compared changes in BMD in adult women using DMPA-IM for contraception or no hormonal contraception, the 2-year post-treatment follow-up demonstrated incomplete recovery of BMD following the last injection of DMPA-IM. Table 4 shows the change in BMD in women after 5 years of treatment with DMPA-IM and in the control group, as well as the extent of BMD recovery in the subset of women for whom 2-year post-treatment data were available.

Table 4. BMD Mean Percent Change from Baseline in Women by Skeletal Site and Cohort (5 Years of Treatment and 2 Years of Follow-Up)
Time in StudySpineTotal HipFemoral Neck
DMPA-IM*Control†DMPA-IM*Control†DMPA-IM*Control†
*
Women who received DMPA-IM for 5 years and were then followed for 2 years post-treatment (total time in study of 7 years).
†
Women who did not use hormonal contraception and were followed for 7 years.

5 years

-5.38%
n=33

0.43%
n=105

-5.16%
n=21

0.19%
n=65

-6.12%
n=34

-0.27%
n=106

7 years

-3.13%
n=12

0.53%
n=60

-1.34%
n=7

0.94%
n=39

-5.38%
n=13

-0.11%
n=63

14.4 Bone Mineral Density Changes in Adolescent Females (12 to 18 years of age) Treated with DMPA-IM

The effect of DMPA-IM on BMD in adolescents is described below, and the effect of depo-subQ provera 104 on BMD in adolescents is expected to be similar. The impact of DMPA-IM use for up to 240 weeks (4.6 years) was evaluated in an open-label non-randomized clinical study in 389 adolescent females (12 to 18 years of age). Use of DMPA-IM was associated with a significant decline from baseline in BMD.

Partway through the trial, DMPA-IM administration was stopped (at 120 weeks). The mean number of injections per DMPA-IM user was 9.3. Table 5 summarizes the study findings. The decline in BMD at total hip and femoral neck was greater with longer duration of use. The mean decrease in BMD at 240 weeks was more pronounced at total hip (-6.4%) and femoral neck (-5.4%) compared to lumbar spine (-2.1%).

Adolescents in the untreated cohort had an increase in BMD during the period of growth following menarche. However, the two cohorts were not matched at baseline for age, gynecologic age, race, BMD, and other factors that influence the rate of acquisition of BMD.

Table 5. BMD Mean Percent Change from Baseline in Adolescents Receiving ≥4 Injections per 60-week Period, by Skeletal Site and Cohort
Duration of TreatmentDMPA-IM (150 mg)Unmatched, Untreated Cohort
NMean % ChangeNMean % Change

Total Hip BMD

Week 60 (1.2 years)

113

-2.75

166

1.22

Week 120 (2.3 years)

73

-5.40

109

2.19

Week 240 (4.6 years)

28

-6.40

84

1.71

Femoral Neck BMD

Week 60

113

-2.96

166

1.75

Week 120

73

-5.30

108

2.83

Week 240

28

-5.40

84

1.94

Lumbar Spine BMD

Week 60

114

-2.47

167

3.39

Week 120

73

-2.74

109

5.28

Week 240

27

-2.11

84

6.40

BMD Recovery Post-Treatment in Adolescents

Longer duration of treatment and smoking were associated with less recovery of BMD following the last injection of DMPA-IM. Table 6 shows the extent of recovery of BMD up to 60 months post-treatment for adolescents who received DMPA-IM for two years or less compared to more than two years. Post-treatment follow-up showed that, in adolescents treated for more than two years, only lumbar spine BMD recovered to baseline levels after treatment was discontinued. Adolescents treated with DMPA-IM for more than two years did not recover to their baseline BMD level at the femoral neck and total hip even up to 60 months post-treatment. Adolescents in the untreated cohort gained BMD throughout the trial period [see Warnings and Precautions (5.1)].

Table 6. BMD Recovery (Months Post-Treatment) in Adolescents by Years of DMPA-IM Use (2 Years or Less vs. More than 2 Years)
Duration of Treatment
(Months)		2 Years or LessMore than 2 Years
NMean % Change from baselineNMean % Change from baseline

Total Hip BMD

End of Treatment

49

-1.5%

49

-6.2%

12 M post-treatment

33

-1.4%

24

-4.6%

24 M post-treatment

18

0.3%

17

-3.6%

36 M post-treatment

12

2.1%

11

-4.6%

48 M post-treatment

10

1.3%

9

-2.5%

60 M post-treatment

3

0.2%

2

-1.0%

Femoral Neck BMD

End of Treatment

49

-1.6%

49

-5.8%

12 M post-treatment

33

-1.4%

24

-4.3%

24 M post-treatment

18

0.5%

17

-3.8%

36 M post-treatment

12

1.2%

11

-3.8%

48 M post-treatment

10

2.0%

9

-1.7%

60 M post-treatment

3

1.0%

2

-1.9%

Lumbar Spine BMD

End of Treatment

49

-0.9%

49

-3.5%

12 M post-treatment

33

0.4%

23

-1.1%

24 M post-treatment

18

2.6%

17

1.9%

36 M post-treatment

12

2.4%

11

0.6%

48 M post-treatment

10

6.5%

9

3.5%

60 M post-treatment

3

6.2%

2

5.7%

14.5 Bone Fracture Incidence in Women Treated with Depo-medroxyprogesterone acetate for Contraception

A retrospective cohort study to assess the association between DMPA-IM injection and the incidence of bone fractures was conducted in 312,395 female contraceptive users in the UK. The incidence rates of fracture were compared between DMPA-IM users and contraceptive users who had no recorded use of DMPA-IM. The Incident Rate Ratio (IRR) for any fracture during the follow-up period (mean=5.5 years) was 1.41 (95% CI 1.35, 1.47). It is not known if this is due to DMPA-IM use or to other related lifestyle factors that have a bearing on fracture rate.

In the study, when cumulative exposure to DMPA-IM was calculated, the fracture rate in users who received fewer than 8 injections was higher than that in women who received 8 or more injections. However, it is not clear that cumulative exposure, which may include periods of intermittent use separated by periods of non-use, is a useful measure of risk, as compared to exposure measures based on continuous use.

There were very few osteoporotic fractures (fracture sites known to be related to low BMD) in the study overall, and the incidence of osteoporotic fractures was not found to be higher in DMPA-IM users compared to non-users.

Importantly, this study could not determine whether use of DMPA-IM has an effect on fracture rate later in life. Given the similar effects on BMD from depo-subQ provera 104 and DMPA-IM described above, bone fracture incidence may also be expected to be similar.

14.6 Bone Mineral Density in Women Treated with depo-SubQ provera 104 for Endometriosis

In two clinical studies of 573 adult women with endometriosis, the BMD effects of 6 months of depo-subQ provera 104 treatment (104 mg subcutaneously every 3 months) were compared to 6 months of leuprolide treatment (either 11.25 mg given subcutaneously every 3 months or 3.75 mg given subcutaneously every month). Subjects were then observed after treatment completion, for an additional 12 months. see Table 7 for the results.

Table 7. BMD Mean Percent Change from Baseline after Therapy for Endometriosis with depo-subQ provera 104 or Leuprolide for 6 Months, and 6- and 12-Months Post-Therapy (Studies 268 and 270 Combined)
Time of BMD MeasurementLumbar SpineTotal Hip
depo-subQ provera 104Leuprolidedepo-subQ provera 104Leuprolide
NMean % ChangeNMean % ChangeNMean % ChangeNMean % Change

Month 6 of treatment (End of Treatment)

208

-1.20

229

-4.10

207

-0.03

227

-1.83

6 months post-treatment

168

-1.06

180

-2.75

169

-0.05

181

-1.59

12 months post-treatment

124

-0.54

133

-1.48

125

0.39

134

-1.15
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