Prospective, randomized, nonblinded trial of 20 patients for the reduction of proteinuria in iMN3
Hladunewich et al, 2014

Overview

This prospective, randomized, non-blinded study assessed the efficacy and safety of Acthar in 20 adult patients (>18 years of age) with biopsy-proven iMN with proteinuria due to nephrotic syndrome (NS).

Primary outcomes included:

  • Changes in the measures of nephrotic syndrome: improvements in proteinuria, serum albumin, and cholesterol profile
  • Documented side effects and toxicity

Secondary endpoints included the proportion of patients who achieved:

  • Complete remission (proteinuria <0.3 g/day)
  • Partial remission (reduction in proteinuria by >50% with final urine protein <3.5 g/day, but >0.3 g/day)
  • No response (reduction in proteinuria by <50%, or worsening of proteinuria)

Inclusion and Exclusion Criteria

Patients with documented resistance to immunosuppressive therapies were excluded. However, patients who had experienced a partial response or had to discontinue immunosuppressive therapies due to significant side effects were eligible to participate.

These patients were required to have discontinued glucocorticoid therapy, calcineurin inhibitors, or mycophenolic mofetil for at least 1 month, and alkylating agents for at least 6 months, prior to the start of the trial.

This served to exclude patients in whom concurrent immunosuppression or a delayed effect of recently discontinued immunosuppression might have a beneficial effect on the disease course as well as to reduce the risk of immunosuppressive complications.

Other exclusion criteria included active infections, secondary causes of iMN, type 1 or type 2 diabetes, pregnant or nursing women, and acute thrombosis requiring anticoagulation therapy.

Study Design

The study was performed at the Mayo Clinic and the University of Toronto. Patients were randomized on a 1:1 ratio to receive 40 or 80 units of Acthar subcutaneously. At the Mayo Clinic site only, patients receiving a 40-unit dose who did not experience significant improvement in urine protein by Day 91 were offered a dose increase to 80 units BIW for an additional 12 weeks (n=5).

*SOC included statin therapy at the maximum recommended dose, dietary counseling to maintain a low-salt diet (2–3 g/day), and dietary protein target intake of 0.8 g/kg ideal body weight/day of high-quality protein.

All study participants had:

  • At least 3 months of treatment with renin-angiotensin system (RAS) blockade to lower blood pressure (BP) to <130/75 mm Hg in >75% of the readings prior to initiation of Acthar
  • No evidence of significant renal insufficiency as defined by eGFR ≥40 mL/min/1.73 m2 while taking RAS blockade

Dosing of Acthar (as stated in Prescribing Information): Dosage and frequency of Acthar should be individualized according to the medical condition, severity of the disease, and initial response of the patient.

  • The usual dose of Acthar is 40 to 80 units given intramuscularly or subcutaneously every 24 to 72 hours

Baseline Characteristics

There were no statistically significant differences in baseline characteristics between the 2 groups. The mean age was 51 years and median disease latency was 14 months.

13 of 20 patients did not receive previous immunosuppressive agents.

Significant improvement in mean proteinuria was observed at treatment completion and at 12-month follow-up

Results

From baseline to the completion of Acthar treatment, there was a significant improvement in mean proteinuria.

Other features of NS such as albumin, total cholesterol, HDL, and LDL were assessed as part of the primary outcomes of the study. eGFR and triglyceride levels were also evaluated.

Acthar significantly reduced mean proteinuria over 12 months, even after treatment was completed

Changes in other relevant measures at treatment completion and at follow-up

*P<0.05 versus baseline.

P<0.05 versus Acthar treatment completion.

  NS=not significant.

Acthar is indicated to reduce proteinuria of nephrotic syndrome. The impact of Acthar on other relevant lab values has not been more formally assessed and is included here for clinical context only.

Changes in proteinuria were observed at treatment completion and at 12-month follow-up*

  • At 12-month follow-up, 12 of the 13 patients who experienced ≥50% reduction in urine protein achieved remission
    • 2 of 13 (10%) had achieved complete remission*
    • 10 of 13 (50%) achieved partial remission, and 1 patient experienced significant improvement in proteinuria, but did not meet criteria for partial remission*
  • The remaining 7 patients had no improvement or progressed with respect to their proteinuria
    • 2 of these 7 patients were given immunosuppression prior to completion of the trial and were excluded from 1-year follow-up data

At 1-year follow-up, more patients in the higher dosing groups (11/16) met remission criteria compared to the low-dose group (1/4)

*Complete remission was defined as proteinuria <0.3 g/day. Partial remission was defined as a reduction in proteinuria by >50% with final urine protein <3.5 g/day, but >0.3 g/day. No response was a reduction in proteinuria by <50%, or worsening of proteinuria.
Cumulative Dose (CD) groups included:
CD 880 IU (n=4): Acthar 40 IU/12 wk.
CD 1760 IU (n=11): Acthar 80 IU/12 wk. CD 2800 IU (n=5): Acthar 40 IU/12 wk followed by Acthar 80 IU/12 wk.

Study limitations

The results may not be fully representative of outcomes in the overall patient population. There was no comparison group for interpretation of safety and efficacy findings with Acthar. Patients received SOC (eg, RAS blockade, statins) during Acthar treatment; thus, the clinical outcomes may not be solely attributable to Acthar. Acthar dosing regimens and duration varied and these limitations should be taken into consideration when interpreting the results.

  • A post hoc assessment of patients, based on the cumulative dose received, revealed a statistically significant trend with respect to improved proteinuria (R=0.53, P<0.05)
    • With respect to dose and response, there was no meaningful change in proteinuria after 12 weeks of therapy in any of the 9 patients initially randomized to the 40-IU dosing group
      • Due to lack of response, 5 of the 9 patients receiving the 40-IU BIW dose were increased to 80 units BIW for an additional 12 weeks (cumulative dose 2800 units)
      • The remaining 4 patients who showed lack of response did not receive additional dosing

A post hoc assessment of patients (based on cumulative dose received) revealed a statistically significant trend with respect to improved proteinuria

Other laboratory values evaluated at 12-month follow-up based on cumulative dose

*P<0.05 for trend across groups.

P<0.05 versus 880 IU.

Acthar is indicated to reduce proteinuria in nephrotic syndrome. The impact of Acthar on other relevant lab values has not been more formally assessed and is included here for clinical context only.

Safety

None of the 20 patients required discontinuation of therapy for treatment-related side effects regardless of dose received. Steroid-related side effects included Cushingoid appearance (n=3), weight gain (n=5), and edema or bloating (n=3). Skin changes included acne (n=2), flushing (n=3), and bronzing (n=2).

Potential psychological effects fluctuated throughout the follow-up period and included increased irritability, depression, and improved mood (n=6). Transient insomnia was also noted (n=6). Bruising at the injection site was also noted (n=5). The following adverse events were described during the year follow-up, but were not in all cases clearly related to the therapy: tremulousness (n=3), hoarseness (n=2), dizziness (n=5), muscle aches or pain (n=5), headaches (n=5), gastrointestinal symptoms (n=7), blurred vision (n=2), and generalized weakness or fatigue (n=9).

Serum blood glucose increased in 13 of 20 patients, but there were no significant differences between the 2 groups. Transient increases to a blood glucose level ≥130 mg/dL occurred in 5 patients, but 1 patient had a clinically important increase in glucose that was sustained and required dietary treatment, but was subsequently improved with weight loss.

Acthar is used to induce a diuresis or a remission of proteinuria in nephrotic syndrome without uremia of the idiopathic type or that due to lupus erythematosus.

Important Safety Information

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Contraindications

  • Acthar should never be administered intravenously
  • Administration of live or live attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of Acthar

Important Safety Information

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Contraindications

  • Acthar should never be administered intravenously
  • Administration of live or live attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of Acthar
  • Acthar is contraindicated where congenital infections are suspected in infants
  • Acthar is contraindicated in patients with scleroderma, osteoporosis, systemic fungal infections, ocular herpes simplex, recent surgery, history of or the presence of a peptic ulcer, congestive heart failure, uncontrolled hypertension, primary adrenocortical insufficiency, adrenocortical hyperfunction or sensitivity to proteins of porcine origins

Warnings and Precautions

  • The adverse effects of Acthar are related primarily to its steroidogenic effects
  • Acthar may increase susceptibility to new infection or reactivation of latent infections
  • Suppression of the hypothalamic-pituitary-axis (HPA) may occur following prolonged therapy with the potential for adrenal insufficiency after withdrawal of the medication. Adrenal insufficiency may be minimized by tapering of the dose when discontinuing treatment. During recovery of the adrenal gland patients should be protected from the stress (e.g. trauma or surgery) by the use of corticosteroids. Monitor patients for effects of HPA suppression after stopping treatment
  • Cushing’s syndrome may occur during therapy but generally resolves after therapy is stopped. Monitor patients for signs and symptoms
  • Acthar can cause elevation of blood pressure, salt and water retention, and hypokalemia. Blood pressure, sodium and potassium levels may need to be monitored
  • Acthar often acts by masking symptoms of other diseases/disorders. Monitor patients carefully during and for a period following discontinuation of therapy
  • Acthar can cause GI bleeding and gastric ulcer. There is also an increased risk for perforation in patients with certain gastrointestinal disorders. Monitor for signs of bleeding
  • Acthar may be associated with central nervous system effects ranging from euphoria, insomnia, irritability, mood swings, personality changes, and severe depression, and psychosis. Existing conditions may be aggravated
  • Patients with comorbid disease may have that disease worsened. Caution should be used when prescribing Acthar in patients with diabetes and myasthenia gravis
  • Prolonged use of Acthar may produce cataracts, glaucoma and secondary ocular infections. Monitor for signs and symptoms
  • Acthar is immunogenic and prolonged administration of Acthar may increase the risk of hypersensitivity reactions. Neutralizing antibodies with chronic administration may lead to loss of endogenous ACTH activity
  • There is an enhanced effect in patients with hypothyroidism and in those with cirrhosis of the liver
  • Long-term use may have negative effects on growth and physical development in children. Monitor pediatric patients
  • Decrease in bone density may occur. Bone density should be monitored for patients on long-term therapy
  • Pregnancy Class C: Acthar has been shown to have an embryocidal effect and should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus

Adverse Reactions

  • Common adverse reactions for Acthar are similar to those of corticosteroids and include fluid retention, alteration in glucose tolerance, elevation in blood pressure, behavioral and mood changes, increased appetite and weight gain
  • Specific adverse reactions reported in IS clinical trials in infants and children under 2 years of age included: infection, hypertension, irritability, Cushingoid symptoms, constipation, diarrhea, vomiting, pyrexia, weight gain, increased appetite, decreased appetite, nasal congestion, acne, rash, and cardiac hypertrophy. Convulsions were also reported, but these may actually be occurring because some IS patients progress to other forms of seizures and IS sometimes mask other seizures, which become visible once the clinical spasms from IS resolve

Other adverse events reported are included in the full Prescribing Information.

Please see full Prescribing Information.

Indication

H.P. Acthar® Gel (repository corticotropin injection) is indicated to induce a diuresis or a remission of proteinuria in nephrotic syndrome without uremia of the idiopathic type or that due to lupus erythematosus.

References